Enhancement of anti-PD-L1 antibody plus anlotinib efficacy due to downregulation of PD-L1 in the micro-conduit endothelium within the tumor:a randomized double-blind trial

Objective:The possible enhancing effect of anlotinib on programmed death receptor ligand(PD-L1)antibody and the efficacy-predicting power of PD-L1 in micro-conduit endothelium,including lymphatic endothelial cells(LECs)and blood endothelial cells(BECs),were determined to identify patients who would benefit from this treatment.Methods:PD-L1 positivity in LECs,BECs,and tumor cells(TCs)was assessed using paraffin sections with multicolor immunofluorescence in an investigator’s brochure clinical trial of TQB2450(PD-L1 antibody)alone or in combination with anlotinib in patients with non-small cell lung cancer.Progression-free survival(PFS)with different levels of PD-L1 expression was compared between the two groups.Results:Among 75 patients,the median PFS(mPFS)was longer in patients who received TQB2450 with anlotinib[10 and 12 mg(161 and 194 days,respectively)]than patients receiving TQB2450 alone(61 days)[hazard ratio(HR)_(10 mg)=0.390(95%confidence interval{CI},0.201–0.756),P=0.005;HR_(12 mg)=0.397(0.208–0.756),P=0.005].The results were similar among 58 patients with high PD-L1 expression in LECs and TCs[159 and 209 vs.82 days,HR_(10 mg)=0.445(0.210–0.939),P=0.034;HR_(12 mg)=0.369(0.174–0.784),P=0.009],and 53 patients with high PD-L1 expression in BECs and TCs[161 and 209 vs.41 days,HR_(10 mg)=0.340(0.156–0.742),P=0.007;HR_(12 mg)=0.340(0.159–0.727),P=0.005].No differences were detected in the mPFS between the TQB2450 and combination therapy groups in 13 low/no LEC-expressing and 18 low/no BEC-expressing PD-L1 cases.Conclusions:Mono-immunotherapy is not effective in patients with high PD-L1 expression in LECs and/or BECs.Anlotinib may increase efficacy by downregulating PD-L1 expression in LECs and/or BECs,which is presumed to be a feasible marker for screening the optimal immune patient population undergoing anti-angiogenic therapy.

Legume green manure can intensify the function of chemical nitrogen fertilizer substitution via increasing nitrogen supply and uptake of wheat

Achieving the green development of agriculture requires the reduction of chemical nitrogen(N)fertilizer input.Previous studies have confirmed that returning green manure to the field is an effective measure to improve crop yields while substituting partial chemical N fertilizer.However,it remains unclear how to further intensify the substituting function of green manure and elucidate its underlying agronomic mechanism.In a split-plot field experiment in spring wheat,different green manures returned to the field under reduced chemical N supply was established in an oasis area since 2018,in order to investigate the effect of green manure and reduced N on grain yield,N uptake,N use efficiency(NUE),N nutrition index,soil organic matter,and soil N of wheat in 2020-2022.Our results showed that mixed sown common vetch and hairy vetch can substitute 40%of chemical N fertilizer without reducing grain yield or N accumulation.Noteworthily,mixed sown common vetch and hairy vetch under reduced N by 20%showed the highest N agronomy efficiency and recovery efficiency,which were 92.0%and 46.0%higher than fallow after wheat harvest and conventional N application rate,respectively.The increase in NUE of wheat was mainly attributed to mixed sown common vetch and hairy vetch,which increased N transportation quantity and transportation rate at pre-anthesis,enhanced N harvest index,optimized N nutrition index,and increased activities of nitrate reductase and glutamine synthetase of leaf,respectively.Meanwhile,mixed sown common vetch and hairy vetch under reduced N by 20%improved soil organic matter and N contents.Therefore,mixed sown common vetch and hairy vetch can substitute 40%of chemical N fertilizer while maintaining grain yield and N accumulation,and it combined with reduced chemical N by 20%or 40%improved NUE of wheat via enhancing N supply and uptake.

A Novel Model for the Prediction of Liquid Film Thickness Distribution in Pipe Gas-Liquid Flows

A model is proposed for liquid film profile prediction in gas-liquid two-phase flow,which is able to provide the film thickness along the circumferential direction and the pressure gradient in the flow direction.A two-fluid model is used to calculate both gas and liquid phases’flow characteristics.The secondary flow occurring in the gas phase is taken into account and a sailing boat mechanism is introduced.Moreover,energy conservation is applied for obtaining the liquid film thickness distribution along the circumference.Liquid film thickness distribution is calculated accordingly for different cases;its values are compared with other models and available experimental data.As a result,the newly proposed model is tested and good performances are demonstrated.The liquid film thickness distribution in small pipes and inclined pipes is also studied,and regime transition is revealed by liquid film profile evolution.The observed inflection point demonstrates that the liquid film thickness decreases steeply along the circumference,when the circle angle ranges between 30°and 50°for gas-liquid stratified flow with small superficial velocities.

Prognostic factors of refractory NSCLC patients receiving anlotinib hydrochloride as the third-or further-line treatment

Objective:Anlotinib hydrochloride is a multitarget tyrosine kinase inhibitor that targets vascular endothelial growth factor receptor,fibroblast growth factor receptor,platelet-derived growth factor receptor,c-Kit,and c-MET;therefore,it exhibits both antitumor and anti-angiogenetic activities.A phase III trial has shown that anlotinib improved progression-free survival(PFS)and overall survival(OS)in patients with advanced non-small cell lung cancer(NSCLC),who presented with progressive disease or intolerance after standard chemotherapy.This study aimed to analyze the characteristics of patients receiving anlotinib treatment to determine the dominant populations who are fit for the treatment.Methods:Data were collected from March 2015 to January 2017 from a randomized,double-blind,placebo-controlled,multicenter,phase III trial of anlotinib(ALTER0303).A total of 437 patients were enrolled and randomly allocated(2:1)to the anlotinib and placebo groups.Kaplan–Meier analysis and log-rank test were performed to compare PFS and OS.Cox proportional hazards model was adopted for multivariate prognostic analysis.Results:Multivariate analysis indicated that high post-therapeutic peripheral blood granulocyte/lymphocyte ratio and elevated alkaline phosphatase levels were independent risk factors for PFS.Meanwhile,elevated thyroid-stimulating hormone,blood glucose,and triglyceride levels;hypertension;and hand–foot syndrome were independent protective factors of PFS.High posttherapeutic peripheral blood granulocyte/lymphocyte ratio,an Eastern Cooperative Oncology Group(ECOG)score≥2,and the sum of the maximal target lesion length at baseline were independent risk factors of OS,and hypertriglyceridemia was an independent protective factor of OS.Conclusions:This study preliminarily explored the possible factors that affected PFS and OS after anlotinib treatment in patients with advanced refractory NSCLC,and the baseline characteristics of the therapeutically dominant populations were then identified.

肺结核导致肺癌的机制研究进展

肺结核和肺癌均严重危害着人类健康,每年分别造成上百万患者死亡.特别在发展中国家,两种疾病均存在较高的发病率.已有流行病学研究证据表明,结核病增加了肺癌的患病风险.肺结核和肺癌预后不同,但在病因方面关系密切.肺结核可以通过慢性炎症刺激、免疫异常、瘢痕及钙化灶、基因突变及药物影响等因素增加肺癌的发生几率.本文就肺结核在肺癌发病机制方面的研究进行综述,为肺结核患者提前进行干预并降低肺癌发生提供参考.

Engineering and microstructure properties of contaminated marine sediments solidified by high content of incinerated sewage sludge ash

Management of incinerated sewage sludge ash(ISSA)and dredged contaminated marine sediments(CMSs)is a great challenge for Hong Kong and other coastal cities due to limited landfilling capacity.The present study investigates the use of high content(20%of sediment by mass)of ISSA in combination with cement/lime for solidification/stabilization(S/S)treatment of CMSs to provide a way to reuse the wastes as construction materials.The results showed that ISSA being a porous material was able to absorb a large amount of water rendering a more efficient solidification process of the marine sediment which normally had a very high water content(w80%).The S/S treatment improved the engineering properties of the sediment,but reduced the workability,especially for the lime-treated samples.Lime can be used to replace ordinary Portland cement(OPC)for better heavy metal immobilization and carbon emission reduction.The hardened sediment samples prepared with 10%of lime and 20%of ISSA could attain a strength of 1.6 MPa after 28 d of curing.In addition,leaching tests confirmed that there was no environmental risk induced by these stabilized materials.The formation of hydrated cementitious compounds including calcium silicate hydrate(CeSeH)/calcium aluminate silicate hydrate(C-A-S-H)/hydrocalumite/calcite was mainly responsible for the strength development in the ISSA/lime-treated sediments.

基于改进MPC的协同自适应巡航控制策略研究

针对环境干扰、传感器噪声和跟随时变车速稳定性较差等问题,提出一种基于KF(kalman filtering)的改进MPC(model predictive control)算法。搭建CACC(cooperative adaptive cruise control)车辆间纵向运动学模型,并建立离散状态空间方程;利用KF对状态变量降噪,同时对预测模型进行鲁棒性设计;对不同工况下CACC控制目标进行分析,分别建立目标优化函数。通过搭建Simulink与CarSim联合仿真模型进行验证,结果表明,改进MPC算法能够提高城市与市郊工况下车辆的燃油经济性与驾乘舒适性,实现公路工况下对时变车速的稳定跟随。

Enhanced Current Transportation in Siliconriched Nitride(SRN)/Silicon-riched Oxide(SRO)Multilayer Nanostructure

A novel structure of silicon-riched nitride(SRN)/silicon-riched oxide(SRO) is proposed and prepared using RF reactive magnetron co-sputtering. High temperature annealing of SRN/SRO multilayers leads to formation of Si nanocrystals(NC) from isolating SRN and SRO layers simultaneously, which efficiently improves carrier transport ability compared to conventional SRN/Si_3N_4 counterpart. Micro-Raman scattering analysis reveals that SRN layer has dominating number of denser and smaller Si NCs, while SRO layer has relatively less, sparser and bigger Si NCs, as confirmed by high resolution transmission electron microscopy observation. The substitute SRO layers for Si_3N_4 counterparts significantly increase the amount of Si NCs as well as crystallization ratio in SRN layers; while the average Si NC size can be well controlled by the thickness of SRN layers and the content of N, and hence an obvious stronger absorption in UV region for the novel structure can be observed in absorption spectra. The I-V characteristics show that the current of hybrid SRN/SRO system increases up to 2 orders of magnitude at 1 V and even 5 orders of magnitude at 4 V compared to that of SRN/Si_3N_4 structure. Si NCs in Si Oylayers provide a transport pathway for adjacent Si NCs in Si Nxlayers. The obvious advantage in carrier transportation suggests that SRN/SRO hybrid system could be a promising structure and platform to build Si nanostructured solar cells.

Relationship of GSTM1 and GSTT1 genetic variant and markers of oxidative stress and inflammation in smokers with coronary artery disease

Objective： To investigate the role of glutathione S-transferase （GST） genetic variants and markers of oxidative stress and inflammation in smokingrelated coronary artery disease （CAD） patients. Methods： Five hundred and thirty-five Chinese CAD patients were successfully genotyped. Plasma total antioxidant status （TAOS）, glutathione, C-reactive protein （CRP）, fibrinogen（FIB） and white blood cell count （WBC） were determined to evaluate the oxidative stress and inflammatory response. Results： GSTM1-0/ GSTT1-0 subjects had a higher CRP, FIB, WBC and GSH and a lower TAOS compared to patients with wild-type GSTM1/GSTT1 genes, but there was significant difference only with regards to TAOS. Smokers with the null genotype of GSTT1 had the highest CRP and the lowest TAOS and GSH when compared to the GSTTI-1 genotype with smoking status, or the GSTT1-0 genotype with non-smoking status, or the GSTTI-I genotype with non-smoking status. However, we found no significant difference between these groups. Also, no significant interaction was observed between genotypes and smoking status in determining CRP levels. Conclusion： Our results suggest that GST polymorphisms do not modify the effect of smoking on markers of oxidative stress and inflammation in Chinese CAD patients.

Synthetic Lethality Induced by a Strong <i>Drosophila</i>Enhancer of Expanded Polyglutamine Tract

Proteins containing an expanded polyglutamine tract are neurotoxins. The expanded polyglutamine proteins influence a variety of cellular functions. In Drosophila the GMR-Gal4/UAS expression system has been widely used in an eye-based model to study human neurodegenerative diseases. This system has facilitated the isolation and characterization of abundant Drosophilagenes that interact with the expanded polyglutamine proteins. We used the GMR-Gal4/UAS system to express three proteins containing an expanded polyglutamine tract, or an expanded polyglutamine tract alone. Doubling the dose of these proteins resulted in pupal lethality, indicating that these toxic proteins induced a sensitized condition that is prone to synthetic lethality. By using the GMR-Gal4/UAS system, we showed that a Drosophilagene interacts with three expanded polyglutamine proteins to induce a synthetic lethal phenotype. We further demonstrated that the synthetic lethality was mediated through the toxic expanded polyglutamine tract. Our study raises a possibility that conventional genetic screens may not recover synthetic lethal alleles, which are presumably stronger interacting alleles than the currently known modifiers of an expanded polyglutamine tract, due to synthetic lethality.

Effects of extracellular vesicle-derived noncoding RNAs on pre-metastatic niche and tumor progression

A pre-metastatic niche(PMN)is a protective microenvironment that facilitates the colonization of disseminating tumor cells in future metastatic organs.Extracellular vesicles(EVs)play a role in intercellular communication by delivering cargoes,such as noncoding RNAs(ncRNAs).The pivotal role of extracellular vesicle-derived noncoding RNAs(EV-ncRNAs)in the PMN has attracted increasing attention.In this review,we summarized the effects of EV-ncRNAs on the PMN in terms of immunosuppression,vascular permeability and angiogenesis,inflammation,metabolic reprogramming,and fibroblast alterations.In particular,we provided a comprehensive overview of the effects of EV-ncRNAs on the PMN in different cancers.Finally,we discussed the promising clinical applications of EV-ncRNAs,including their potential as diagnostic and prognostic markers and therapeutic targets.

Research advances in peptide-drug conjugates

Peptide-drug conjugates(PDCs)are drug delivery systems consisting of a drug covalently coupled to a multifunctional peptide via a cleavable linker.As an emerging prodrug strategy,PDCs not only preserve the function and bioactivity of the peptides but also release the drugs responsively with the cleavable property of the linkers.Given the ability to significantly improve the circulation stability and targeting of drugs in vivo and reduce the toxic side effects of drugs,PDCs have already been extensively applied in drug delivery.Herein,we review the types and mechanisms of peptides,linkers and drugs used to construct PDCs,and summarize the clinical applications and challenges of PDC drugs.

A new method for evaluating the oil mobility based on the relationship between pore structure and state of oil

An accurate evaluation of the shale oil mobility is crucial to its cost-effective exploitation.This study presents a method to assess shale oil mobility by integrating the pore structure and oil states distributions.First,a set of three discrete organic extracts(EOM-A,B and C)were obtained by sequential extraction.The relationships among the EOMs and the oil states were inferred from the group compositions and fluorescence properties of the produced shale oil(free state).The results showed that EOMs A and B represent free oil in the open and closed pores,respectively,while the EOM-C represents adsorbed oil.Then,NMR T_(1)-T_(2)map is used to determine the T_(2-cutoff)values that indicate the pore size ranges of different oil states.Free oil resides mainly in larger pore space(T_(2)>0.5 ms),while the adsorbed oil in smaller pore space(0.2 ms<T_(2)<0.5 ms).Finally,the ratio of free to adsorbed oil(F/A)>0.5 and T_(2-cutoff)>1.0 ms suggest that the free oil in connected pores has the highest mobility.This work can provide a reference for evaluating the shale oil potential and prospectivity in other regions.

Complex-amplitude radiation-type metasurface enabling beamform-controlled energy allocation

Fifth-generation(5G)communication requires spatial multiplexing multiple-input multiple-output systems with integrated hardware.With the increase in the number of users and emergence of the Internet of Things devices,complex beamforming devices have become particularly important in future wireless systems to meet different communication requirements,where independent amplitude and phase modulations are urgently required for integrated beamforming devices.Herein,by utilizing the constructive interference between multiple geometricphase responses,the mathematical relation for decoupling amplitude and phase modulations in the radiation-type operational mode is derived.Based on this strategy,complex-amplitude radiation-type metasurfaces(RA-Ms)are implemented,with an integrated feeding network.Such metasurfaces exploit full 2πphase modulation and tailorable radiation amplitude in the circular polarization state.Meanwhile,a complex-amplitude retrieval method is developed to design the RA-Ms,enabling precise beamforming performances.On this basis,several functional devices based on the complex-amplitude RA-Ms,including energy-allocable multi-router,shape-editable beam generator,and complex beamformer,are demonstrated in the microwave region.The amplitude-phase decoupling mechanism with the retrieval method merges amplitude and phase modulations,and energy distribution into one compact and integrated electromagnetic component and may find applications in multi-target detection,5G mobile communication,and short-range ground-to-sea radar.

Third-line or above anlotinib in relapsed and refractory small cell lung cancer patients with brain metastases:A post hoc analysis of ALTER1202,a randomized,double-blind phase 2 study

Background:The prognosis of patients with small cell lung cancer(SCLC)and brain metastases(BM)was poor.This study aimed to explore the efficacy and safety of anlotinib as third-line or above treatment in SCLC with BM.Methods:This was a subgroup analysis of the ALTER1202 trial,which was a randomized,placebo-controlled trial aimed to evaluate the role of anlotinib as third-line treatment or above in patients with SCLC.This study included patients with BM at baseline.The efficacy and safety outcomes included progression-free survival(PFS),overall survival(OS),central nervous system(CNS),objective response rate(ORR),CNS disease control rate(DCR),time to CNS progression,and adverse events(AEs).Results:Twenty-one and nine patients with BM were included in the anlotinib and placebo groups,respectively.The median PFS and OS were 3.8 months(95%confidence interval[CI]:1.8-6.1)and 6.1 months(95%CI:4.1-8.0)in the anlotinib group.Anlotinib was associated with a significant improvement in PFS(hazard ratio[HR]=0.15,95%CI:0.04-0.51,p=0.0005)and OS(HR=0.26,95%CI:0.09-0.73,p=0.0061)than placebo.Anlotinib significantly prolonged the time to CNS progression(p<0.0001).The anlotinib group had a higher CNS DCR than placebo(95.2%vs.22.2%,p=0.0001).The most common grade 3 or higher AEs were increased lipase(19.0%),hypertension(14.3%),and hyponatremia(14.3%)in the anlotinib group.Conclusions:Anlotinib proved to have potential CNS activity and a manageable toxicity profile in patients with SCLC and BM,significantly delaying CNS progression.

Sliding-mode-based preassigned-time control of a class of memristor chaotic systems

This paper addresses the preassigned-time chaos control problem of memristor chaotic systems with time delays.Since the introduction of memristor,the presented models are nonlinear systems with chaotic dynamics.First,the TS fuzzy method is adopted to describe the chaotic systems.Then,a sliding-model-based control approach is proposed to achieve the preassigned-time stabilization of the presented models,where the upper bound of stabilization time can be arbitrarily specified in advance.Finally,simulation results demonstrate the validity of presented control approach and theoretic results.

Central nervous system efficacy of aumolertinib versus gefitinib in patients with untreated,EGFR-mutated,advanced non-small cell lung cancer:data froma randomized phase III trial(AENEAS)

Background:The initial randomized,double-blinded,actively controlled,phase III ANEAS study(NCT03849768)demonstrated that aumolertinib showed superior efficacy relative to gefitinib as first-line therapy in epidermal growth factor receptor(EGFR)-mutated advanced non-small cell lung cancer(NSCLC).Metastatic disease in the central nervous system(CNS)remains a challenge in the management of NSCLC.This study aimed to compare the efficacy of aumolertinib versus gefitinib among patients with baseline CNS metastases in the ANEAS study.Methods:Eligible patients were enrolled and randomly assigned in a 1:1 ratio to orally receive either aumolertinib or gefitinib in a double-blinded fashion.Patients with asymptomatic,stable CNS metastases were included.Follow-up imaging of the same modality as the initial CNS imaging was performed every 6 weeks for 15 months,then every 12weeks.CNS responsewas assessed by a neuroradiological blinded,independent central review(neuroradiological-BICR).The primary endpoint for this subgroup analysis was CNS progression-free survival(PFS).Results:Of the 429 patients enrolled and randomized in the ANEAS study,106 patients were found to have CNS metastases(CNS Full Analysis Set,cFAS)at baseline by neuroradiological-BICR,and 60 of them had CNS target lesions(CNS Evaluable for Response,cEFR).Treatment with aumolertinib significantly prolonged median CNS PFS compared with gefitinib in both cFAS(29.0 vs.8.3 months;hazard ratio[HR]=0.31;95%confidence interval[CI],0.17-0.56;P<0.001)and cEFR(29.0 vs.8.3 months;HR=0.26;95%CI,0.11-0.57;P<0.001).The confirmed CNS overall response rate in cEFRwas 85.7%and 75.0%in patients treated with aumolertinib and gefitinib,respectively.Competing risk analysis showed that the estimated probability of CNS progression without prior non-CNS progression or death was consistently lower with aumolertinib than with gefitinib in patients with and without CNSmetastases at baseline.No new safety findings were observed.Conclusions:These results indicate a potential advantage of aumolertinib over gefitinib in terms of CNS PFS and the risk of CNS progression in patients with EGFR-mutated advanced NSCLC with baseline CNS metastases.

Commissioning progress of the FAST

The Five-hundred-meter Aperture Spherical radio Telescope(FAST) was completed with its main structure installed on September 25, 2016, after which it entered the commissioning phase. This paper aims to introduce the commissioning progress of the FAST over the past two years. To improve its operational reliability and ensure effective observation time, FAST has been equipped with a real-time information system for the active reflector system and hierarchical commissioning scheme for the feed support system, which ultimately achieves safe operation of the two systems. For meeting the high-performance indices, a highprecision measurement system was set up based on the effective control methods that were implemented for the active reflector system and feed support system. Since the commissioning of the FAST, a low-frequency ultra-wideband receiver and 19-beam1.05-1.45 GHz receiver have been mainly used. Telescope efficiency, pointing accuracy, and system noise temperature were completely tested and ultimately achieved the acceptance indices of the telescope. The FAST has been in the process of national acceptance preparations and has begun to search for pulsars. In the future, it will still strive to improve its capabilities and expand its application prospects.

Nanocarrier-mediated co-delivery of chemotherapeutic drugs and gene agents for cancer treatment

The efficacy of chemotherapeutic drug in cancer treatment is often hampered by drug resistance of tumor cells,which is usually caused by abnormal gene expression.RNA interference mediated by si RNA and mi RNA can selectively knock down the carcinogenic genes by targeting specific m RNAs.Therefore,combining chemotherapeutic drugs with gene agents could be a promising strategy for cancer therapy.Due to poor stability and solubility associated with gene agents and drugs,suitable protective carriers are needed and have been widely researched for the co-delivery.In this review,we summarize the most commonly used nanocarriers for co-delivery of chemotherapeutic drugs and gene agents,as well as the advances in co-delivery systems.

Multifunctional oral delivery systems for enhanced bioavailability of therapeutic peptides/proteins

In last few years, therapeutic peptides/proteins are rapidly growing in drug market considering their higher efficiency and lower toxicity than chemical drugs. However, the administration of therapeutic peptides/proteins is mainly limited in parenteral approach. Oral therapy which was hampered by harsh gastrointestinal environment and poorly penetrating epithelial barriers often results in low bioavailability(less than 1%–2%). Therefore, delivery systems that are rationally designed to overcome these challenges in gastrointestinal tract and ameliorate the oral bioavailability of therapeutic peptides/proteins are seriously promising. In this review, we summarized various multifunctional delivery systems, including lipid-based particles, polysaccharide-based particles, inorganic particles, and synthetic multifunctional particles that achieved effective oral delivery of therapeutic peptides/proteins.