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Development of small molecule drugs targeting immune checkpoints

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Cancer Biology & Medicine 2024年第5期21卷 382-399页

作者： Luoyi Chen Xinchen Zhao Xiaowei liu Yujie Ouyang Chuan xu Ying shi Department of Oncology Sichuan Academy of Medical SciencesSichuan Provincial People’s HospitalSchool of MedicineUniversity of Electronic Science and Technology of ChinaChengdu 610054China Institute for Breast Health Medicine State Key Laboratory of BiotherapyWest China HospitalSichuan UniversityChengdu 610041China Acupuncture and Massage College Chengdu University of Traditional Chinese MedicineChengdu 611137China

Immune checkpoint inhibitors(ICIs)are used to relieve and refuel anti-tumor immunity by blocking the interaction,transcription,and translation of co-inhibitory immune checkpoints or degrading co-inhibitory immune checkpoints.Thousands of small molecule drugs or biological materials,especially antibody-based ICIs,are actively being studied and antibodies are currently widely used.Limitations,such as anti-tumor efficacy,poor membrane permeability,and unneglected tolerance issues of antibody-based ICIs,remain evident but are thought to be overcome by small molecule drugs.Recent structural studies have broadened the scope of candidate immune checkpoint molecules,as well as innovative chemical inhibitors.By way of comparison,small molecule drug-based ICIs represent superior oral bioavailability and favorable pharmacokinetic features.Several ongoing clinical trials are exploring the synergetic effect of ICIs and other therapeutic strategies based on multiple ICI functions,including immune regulation,anti-angiogenesis,and cell cycle regulation.In this review we summarized the current progression of small molecule ICIs and the mechanism underlying immune checkpoint proteins,which will lay the foundation for further exploration.

关键词： Immune checkpoints small molecule drugs programmed death protein 1 CD47 signal-regulatory proteinα

High-speed penetration of ogive-nose projectiles into thick concrete targets:Tests and a projectile nose evolution model

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Defence Technology（防务技术） 2024年第2期32卷 553-571页

作者： xu Li Yan liu Junbo Yan Zhenqing shi Hongfu Wang Yingliang xu Fenglei Huang State Key Laboratory of Explosion Science and Technology Beijing Institute of TechnologyBeijing100081China Beijing Institute of Technology Chongqing Innovation Center Chongqing401120China China Research and Development Academy of Machinery Equipment Beijing100089China

The majority of the projectiles used in the hypersonic penetration study are solid flat-nosed cylindrical projectiles with a diameter of less than 20 mm.This study aims to fill the gap in the experimental and analytical study of the evolution of the nose shape of larger hollow projectiles under hypersonic penetration.In the hypersonic penetration test,eight ogive-nose AerMet100 steel projectiles with a diameter of 40 mm were launched to hit concrete targets with impact velocities that ranged from 1351 to 1877 m/s.Severe erosion of the projectiles was observed during high-speed penetration of heterogeneous targets,and apparent localized mushrooming occurred in the front nose of recovered projectiles.By examining the damage to projectiles,a linear relationship was found between the relative length reduction rate and the initial kinetic energy of projectiles in different penetration tests.Furthermore,microscopic analysis revealed the forming mechanism of the localized mushrooming phenomenon for eroding penetration,i.e.,material spall erosion abrasion mechanism,material flow and redistribution abrasion mechanism and localized radial upsetting deformation mechanism.Finally,a model of highspeed penetration that included erosion was established on the basis of a model of the evolution of the projectile nose that considers radial upsetting;the model was validated by test data from the literature and the present study.Depending upon the impact velocity,v0,the projectile nose may behave as undistorted,radially distorted or hemispherical.Due to the effects of abrasion of the projectile and enhancement of radial upsetting on the duration and amplitude of the secondary rising segment in the pulse shape of projectile deceleration,the predicted DOP had an upper limit.

关键词： High-speed penetration Concrete target Erosion Projectile nose evolution model

Polyimide covalent organic frameworks as efficient solid-state Li^(+) electrolytes

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Science China Chemistry 2024年第5期67卷 1647-1652页

作者： xu liu shi Wang Siqi liu Chengfang liu Xiangchun Li Jian Wu Dazhi Li shihao xu Chongyang liu Wen-Yong Lai State Key Laboratory of Organic Electronics and Information Displays(SKLOEID) Institute of Advanced Materials(IAM)School of Chemistry and Life SciencesNanjing University of Posts&TelecommunicationsNanjing 210023China

Covalent organic frameworks(COFs) are attractive porous crystalline materials with extremely high stability, easy functionalization, and open channels, which are expected to be unique ion conductors/transporters in lithium ion batteries(LIBs). Despite recent advances, low ion conductivity and low transference number, resulting in low charging/discharging rate, low energy density, and short battery life, are the main issues that limit their direct application as solid electrolytes in LIBs. Here, we designed and synthesized a novel polyimide COF, namely, TAPA-PDI-COF, with abundant C=O groups, which has been successfully employed as high-performance solid electrolytes by doping TAPA-PDI-COF and succinonitrile(SN). Both the well-defined nanochannels of COFs and SN confined in the well-aligned channels restricted the free migration of anions, while C=O on COFs and CN groups of SN enhanced Li^(+) transport, thus achieving a high ion conductivity of 0.102 m S cm^(-1)at 80 °C and a high lithium-ion transference number of 0.855 at room temperature. According to density functional theory(DFT)calculations, Li-ion migration mainly adopted in-plane transport rather than the axial pathway, which may be due to the shorter hopping distances in the planar pathway. The results suggest an effective strategy for the design and development of all-solidstate ionic conductors for achieving high-performance LIBs.

关键词： lithium ion batteries(LIBs) covalent organic frameworks(COFs) solid-state ion conductors solid-state electrolytes ion conductivity

Riverine sulfate sources and behaviors in arid environment,Northwest China:Constraints from sulfur and oxygen isotopes

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Journal of Environmental Sciences 2024年第3期137卷 716-731页

作者： Yifu xu Wenjing liu Bing xu Zhifang xu Key Laboratory of Cenozoic Geology and Environment Institute of Geology and GeophysicsChinese Academy of SciencesBeijing 100029China Innovation Academy for Earth Science Chinese Academy of SciencesBeijing 100029China University of Chinese Academy of Sciences Beijing 100049China

The fate of riverine sulfate ion (SO_(4)^(2-)) and its environmental effects in arid environment are difficult to evaluate due to its complicated sources and strongly coupled behaviors with water cycle which is significantly modified by humans.To understand the sulfur cycle in aquatic systems in arid environment,the chemical and sulfur and oxygen isotopic compositions (δ^(34)S_(SO4)and δ^(18)O_(SO4)) of major rivers around the Badain Jaran Desert,northwestern China,were investigated.These rivers had averaged SO_(4)^(2-)content at 1336μmol/L,over 10times higher than the global average.The δ^(34)S_(SO4)and δ^(18)O_(SO4)values ranged from-5.3‰to+11.8‰and+1.6‰to+12.8‰,respectively.The end-member analysis and the inverse model showed that riverine sulfate was mainly derived from evaporites dissolution (0-87%),sulfide oxidation (13%-100%) and precipitation (0-33%),indicating heterogeneity in sulfur sources and behaviors along the river drainage with the lithology variations and climate gradients.Multiple isotopic tools combining with hydro-chemistry compositions could be applied to reveal sulfur cycle in arid environment.Based on the calculation,sulfide oxidation plays the primary role in the headwater and upstream in the Qilian-Mountains area,where sulfide is widely exposed.While the proportion of evaporites dissolution contributing to riverine sulfate is much higher in downstream in a drier environment.Besides,less precipitation and higher temperature can lead to more intensive evaporation,affecting the process of sulfide oxidation and enhancing the rates of evaporites dissolution and sulfate precipitation in the basin.

关键词： Sulfur and oxygen isotopes Source apportionment Inverse model Arid environment Inland rivers Northwestern China

Experimental and numerical analyses of the effect of fibre content on the close-in blast performance of a UHPFRC beam

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Defence Technology（防务技术） 2024年第1期31卷 242-261页

作者： Junbo Yan Qiyue Zhang Yan liu Yingliang xu Zhenqing shi Fan Bai Fenglei Huang State Key Laboratory of Explosion Science and Technology Beijing Institute of TechnologyBeijing 100081China Beijing Institute of Technology Chongqing Innovation Center Chongqing 401120China

Limited research has been conducted on the influences of fiber content on close-in blasting characteristics for ultrahigh-performance fiber-reinforced concrete(UHPFRC)beams.This paper aims to address this knowledge gap through experimental and mesoscale numerical methods.Experiments were conducted on ten UHPFRC beams built with varying steel fiber volumetric fractions subjected to close-in explosive conditions.Additionally,this study considered other parameters,such as the longitudinal reinforcement type and ratio.In the case of UHPFRC beams featuring normal-strength longitudinal reinforcement of diametersΦ12,Φ16,andΦ20,a reduction in maximum displacement by magnitudes of19.6%,19.5%,and 17.4%was observed,respectively,as the volumetric fractions of fiber increased from1.0%to 2.5%.In addition,increasing the longitudinal reinforcement ratio and using high-strength steel longitudinal reinforcement both significantly reduced the deformation characteristics and increase the blasting resistances of UHPFRC beams.However,the effects on the local crushing and spalling damage were not significant.A mesoscale finite element model,which considers the impacts of fiber parameters on UHPFRC beam behaviors,was also established and well correlated with the test findings.Nevertheless,parametric analyses were further conducted to examine the impacts of the steel fiber content and length and the hybrid effects of various types of microfibers and steel fibers on the blasting performance of UHPFRC beams.

关键词： Blast performance Close-in blast Fiber content Mesoscale approach UHPFRC beams

Preventive effects of Bifidobacterium lactis Probio-M8 on ovalbumin-induced food allergy in mice

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Food Science and Human Wellness 2024年第4期13卷 2346-2352页

作者： Jialu shi Yan xu Cheng liu shizhi Wang Jin Wang Vijaya Raghavan Key Laboratory of Environmental Medicine and Engineering Ministry of Educationand Department of Nutrition and Food HygieneSchool of Public HealthSoutheast UniversityNanjing 210009China Department of Bioresource Engineering Faculty of Agricultural and Environmental SciencesMcGill UniversitySainte-Anne-de-BellevueQC H9X3V9Canada

Food allergy is a significant public health concern globally.Certain probiotics have been found to enhance food allergy by regulating immune-microbe interactions in animal models and patients.However,the effects of Bifidobacterium lactis Probio-M8 on food allergy have not been thoroughly investigated.The present study examined the anti-allergic properties of Probio-M8,particularly in relation to immune response and gut microbiota composition.Results demonstrate that oral administration of Probio-M8 effectively mitigated the allergy symptoms triggered by ovalbumin(OVA)by ameliorating the morphological damage in the jejunum,reducing OVA-specific IgE and histamine levels in the serum,and suppressing Th2 cytokines(interleukin(IL)4 and IL-13)while increasing Th1 cytokines(interferon(IFN)γ)and regulatory T(Treg)cytokines(IL-10 and transforming growth factor(TGF)β1)in the culture supernatants of splenic cells.Furthermore,Probio-M8 effectively altered the diversity and composition of gut microbiota,particularly the relative abundances of Akkermansia_muciniphila in OVA-induced mice.Compared to the OVA group,the Probio-M8 group showed a decrease in the relative abundance of Akkermansia_muciniphila.In conclusion,Probio-M8 demonstrates the potential to alleviate food allergy by regulating the Th1/Th2 response and modulating gut microbiota,thereby offering a novel therapeutic strategy for patients with food allergy.

关键词： Food allergy Bifidobacterium lactis Probio-M8 T cell immune response Gut microbiota

Giant bile duct dilatation in newborn:A case report

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World Journal of Clinical Cases 2024年第6期12卷 1150-1156页

作者： Dong-Wen Quan Peng-Gang Li Xiang-Hua xu shi-Qi liu The Second Clinical Medical School Shaanxi University of Chinese MedicineXianyang 712000Shaanxi ProvinceChina The First School of Clinical Medicine Shaanxi University of Chinese MedicineXianyang 712000Shaanxi ProvinceChina Department of Hepatobiliary Surgery The First Affiliated Hospital of Xi’an Jiaotong UniversityXi’an 710061Shaanxi ProvinceChina Department of Neonatal Surgery Xi’an Children’s Hospital Affiliated Xi’an Jiaotong UniversityXi’an 710003Shaanxi ProvinceChina

BACKGROUND Giant congenital biliary dilation(CBD)is a rare condition observed in clinical practice.Infants born with this condition often experience a poor overall health status,and the disease progresses rapidly,leading to severe biliary obstruction,infections,pressure exerted by the enlarged CBD on abdominal organs,disturbances in the internal environment,and multiple organ dysfunction.The treatment of giant CBD using laparoscopy is challenging due to the high degree of variation in the shape of the bile duct and other organs,making it difficult to separate the bile duct wall from adjacent tissues or to control bleeding.CASE SUMMARY Herein,we present the details of an 11-d-old male newborn who was diagnosed with giant CBD.The patient was admitted to the neonatal surgery department of our hospital due to a history of common bile duct cyst that was detected more than 3 mo ago,and also because the patient had been experiencing yellowish skin for the past 9 d.The abnormal echo in the fetal abdomen was first noticed by the patient’s mother during a routine ultrasound examination at a local hospital,when the patient was at 24 wk+6 d of pregnancy.This finding raised concerns about the possibility of congenital biliary dilatation(22 mm×21 mm).Subsequent ultrasound examinations at different hospitals consistently confirmed the presence of a congenital biliary dilatation.No specific treatment was administered for biliary dilatation during this period.A computed tomography scan conducted during the hospitalization revealed a large cystic mass in the right upper quadrant and pelvis,measuring approximately 9.2 cm×7.4 cm×11.3 cm.Based on the CONCLUSION The analysis reveals that prenatal imaging techniques,such as ultrasound and magnetic resonance imaging,play a crucial role in the early diagnosis,fetal prognosis,and treatment plan for giant CBD.Laparoscopic surgery for giant CBD presents certain challenges,including difficulties in separating the cyst wall,anastomosis,and hemostasis,as well as severe biliary system infection

关键词： Acute cholangitis Congenital biliary dilation Laparoscopic surgery vs Open hepatic duct-jejunostomy Case report

An investigation on topologies of hybrid manifold,impinging-jet nozzle and micro-pin-fin heat sinks

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Science China(Technological Sciences) 2024年第4期67卷 1061-1076页

作者： shi QianLei YAO XiaoLe liu Qian QIN Le JU Xing xu Chao Key Laboratory of Power Station Energy Transfer Conversion and System of MOE North China Electric Power UniversityBeijing 102206China

The hybrid manifold micro-pin-fin(MMPF)heat sink combined nozzle jets is an option for large-scale integrated circuits(LSI).The demond for uniform and ultra-high heat flux removal by MMPF heat sink has not been adequately investigated.This work aims to solve the problem of fluid organization.The proposed basic tiling topologies,including square,regular hexagon,30°rhombus,and 60°rhombus topologies,provide different organized fluid flows and heat transfer patterns.The present study focuses on comparing these topologies according to independent porous medium parameters,such as nozzle pore size D_(Z),flow pore size D_(X,Y),and porosityε.The results show that the square topology achieves the smallest total thermal resistance R_(tot)value of0.0975×10^(-4)K m^2/W,while the hexagon topology achieved the highest value of COP/?T,which was 2033.9 K^(-1).According to the sensitivity analysis results,the optimal total thermal resistance can be obtained by balancing the influences of nozzle pore size,flow pore size,and porosity.The optimal pressure drop can be obtained by maximizing the porosity.

关键词： heat sink ultra-high heat flux manifold micro-pin-fin impinging-jet topology

Circulating tumor DNA in liquid biopsy: Current diagnostic limitation

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World Journal of Gastroenterology 2024年第15期30卷 2175-2178页

作者： shi-Cai liu School of Medical Information Wannan Medical CollegeWuhu 241002Anhui ProvinceChina

With the rapid development of science and technology,cell-free DNA(cfDNA)is rapidly becoming an important biomarker for tumor diagnosis,monitoring and prognosis,and this cfDNA-based liquid biopsy technology has great potential to become an important part of precision medicine.cfDNA is the total amount of free DNA in the systemic circulation,including DNA fragments derived from tumor cells and all other somatic cells.Tumor cells release fragments of DNA into the bloodstream,and this source of cfDNA is called circulating tumor DNA(ctDNA).cfDNA detection has become a major focus in the field of tumor research in recent years,which provides a new opportunity for non-invasive diagnosis and prognosis of cancer.In this paper,we discuss the limitations of the study on the origin and dynamics analysis of ctDNA,and how to solve these problems in the future.Although the future faces major challenges,it also con-tains great potential.

关键词： Cell-free DNA Circulating tumor DNA Liquid biopsy Cancer Diagnosis Prognosis