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New clinical trial design in precision medicine:discovery,development and direction

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Signal Transduction and Targeted Therapy 2024年第4期9卷 1293-1321页

作者： Xiao-Peng Duan Bao-Dong Qin Xiao-Dong Jiao ke liu Zhan Wang Yuan-Sheng Zang Department of Medical Oncology Changzheng HospitalNaval Medical UniversityShanghaiChina

In the era of precision medicine,it has been increasingly recognized that individuals with a certain disease are complex and different from each other.Due to the underestimation of the significant heterogeneity across participants in traditional"one-sizefits-all"trials,patient-centered trials that could provide optimal therapy customization to individuals with specific biomarkers were developed including the basket,umbrella,and platform trial designs under the master protocol framework.In recent years,the successive FDA approval of indications based on biomarker-guided master protocol designs has demonstrated that these new clinical trials are ushering in tremendous opportunities.Despite the rapid increase in the number of basket,umbrella,and platform trials,the current clinical and research understanding of these new trial designs,as compared with traditional trial designs,remains limited.The majority of the research focuses on methodologies,and there is a lack of in-depth insight concerning the underlying biological logic of these new clinical trial designs.Therefore,we provide this comprehensive review of the discovery and development of basket,umbrella,and platform trials and their underlying logic from the perspective of precision medicine.Meanwhile,we discuss future directions on the potential development of these new clinical design in view of the"Precision Pro","Dynamic Precision",and"Intelligent Precision".This review would assist trial-related researchers to enhance the innovation and feasibility of clinical trial designs by expounding the underlying logic,which be essential to accelerate the progression of precision medicine.

关键词： clinical approval successive

Synergistic Effects of Carbon Nanotube(CNT)and Reduced Graphene Oxide(RGO)on Mechanical and Thermal Properties of ZK61 Alloy

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Acta Metallurgica Sinica(English Letters) 2024年第3期37卷 577-585页

作者： Fanjing Meng Wenbo Du Ning Ding Jian Sun Xian Du ke liu Shubo Li College of Materials Science and Engineering Faculty of Materials and ManufacturingBeijing University of TechnologyBeijing 100124China

The hybrid of carbon nanotube(CNT)and reduced graphene oxide(RGO)reinforced ZK61 composite was fabricated by a hot extrusion process.Compared with the raw ZK61 alloy and single-reinforced composites,the hybrid-reinforced by RGO+CNT complex exhibited significant enhancements both in mechanical and thermal performance.By adjusting the proportion of RGO and CNT in ZK61 alloy,the obtained optimum ZK61/(0.06 wt%RGO+0.54 wt%CNT)composite exhibited increase of 25.4%in yield strength,26.5%in ultimate tensile strength,104%in failure strain and 30.4%in thermal conductivity,respectively,in comparison with ZK61 alloy.The superior properties of the nano-hybrid composite are attributed to the synergetic effects of RGO and CNT,leading to a uniform dispersion and integrated structure as well as the enhanced interfacial bonding with matrix.The strengthening ability of RGO and CNT was calculated to quantify their individual contribution to the improvement in mechanical and thermal properties of the ZK61 matrix composite.The RGO+CNT hybrids provide a promising way to develop Mg matrix composites with impressive performances.

关键词： Mg matrix composite Carbon nanotube Reduced graphene oxide Mechanical performance Thermal conductivity

Topological reorganization and functional alteration of distinct genomic components in gallbladder cancer

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Frontiers of Medicine 2024年第1期18卷 109-127页

作者： Guoqiang Li Peng Pu Mengqiao Pan Xiaoling Weng Shimei Qiu Yiming Li Sk Jahir Abbas Lu Zou ke liu Zheng Wang Ziyu Shao Lin Jiang Wenguang Wu Yun liu Rong Shao Fatao liu Yingbin liu Department of Biliary-Pancreatic Surgery Renji HospitalSchool of MedicineShanghai Jiao Tong UniversityShanghai200127China State key Laboratory of Oncogenes and Related Genes Shanghai Cancer InstituteShanghai200127China Shanghai key Laboratory of Biliary Tract Disease Shanghai200082China Department of Health Science and Engineering University of Shanghai for Science and TechnologyShanghai200082China Shanghai Tenth People’s Hospital of Tongji University Shanghai200072China Department of General Surgery Xinhua HospitalSchool of MedicineShanghai Jiao Tong UniversityShanghai200082China Department of Pharmacology Shanghai Jiao Tong University School of MedicineShanghai200025China

Altered three-dimensional architecture of chromatin influences various genomic regulators and subsequent gene expression in human cancer.However,knowledge of the topological rearrangement of genomic hierarchical layers in cancer is largely limited.Here,by taking advantage of in situ Hi-C,RNA-sequencing,and chromatin immunoprecipitation sequencing(ChIP-seq),we investigated structural reorganization and functional changes in chromosomal compartments,topologically associated domains(TADs),and CCCTC binding factor(CTCF)-mediated loops in gallbladder cancer(GBC)tissues and cell lines.We observed that the chromosomal compartment A/B switch was correlated with CTCF binding levels and gene expression changes.Increased inter-TAD interactions with weaker TAD boundaries were identified in cancer cell lines relative to normal controls.Furthermore,the chromatin short loops and cancer unique loops associated with chromatin remodeling and epithelial–mesenchymal transition activation were enriched in cancer compared with their control counterparts.Cancer-specific enhancer–promoter loops,which contain multiple transcription factor binding motifs,acted as a central element to regulate aberrant gene expression.Depletion of individual enhancers in each loop anchor that connects with promoters led to the inhibition of their corresponding gene expressions.Collectively,our data offer the landscape of hierarchical layers of cancer genome and functional alterations that contribute to the development of GBC.

关键词： 3D genome cancer TADs loop gene regulation

Small but mighty:Empowering sodium/potassium-ion battery performance with S-doped SnO2 quantum dots embedded in N,S codoped carbon fiber network

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Carbon Energy 2024年第5期6卷 186-200页

作者： Shengnan He Hui Wu Shuang Li ke liu Yaxiong Yang Hongge Pan Xuebin Yu Institute of Science and Technology for New Energy Xi'an Technological UniversityXi'anChina Department of Materials Science Fudan UniversityShanghaiChina Wanxiang A123 Systems Corporation HangzhouChina School of Material Science and Engineering Shanghai UniversityShanghaiChina

SnO_(2) has been extensively investigated as an anode material for sodium-ion batteries(SIBs)and potassium-ion batteries(PIBs)due to its high Na/K storage capacity,high abundance,and low toxicity.However,the sluggish reaction kinetics,low electronic conductivity,and large volume changes during charge and discharge hinder the practical applications of SnO_(2)-based electrodes for SIBs and PIBs.Engineering rational structures with fast charge/ion transfer and robust stability is important to overcoming these challenges.Herein,S-doped SnO_(2)(S-SnO_(2))quantum dots(QDs)(≈3 nm)encapsulated in an N,S codoped carbon fiber networks(S-SnO_(2)-CFN)are rationally fabricated using a sequential freeze-drying,calcination,and S-doping strategy.Experimental analysis and density functional theory calculations reveal that the integration of S-SnO_(2) QDs with N,S codoped carbon fiber network remarkably decreases the adsorption energies of Na/K atoms in the interlayer of SnO_(2)-CFN,and the S doping can increase the conductivity of SnO_(2),thereby enhancing the ion transfer kinetics.The synergistic interaction between S-SnO_(2) QDs and N,S codoped carbon fiber network results in a composite with fast Na+/K+storage and extraordinary long-term cyclability.Specifically,the S-SnO_(2)-CFN delivers high rate capacities of 141.0 mAh g^(−1) at 20 A g^(−1) in SIBs and 102.8 mAh g^(−1) at 10 A g^(−1) in PIBs.Impressively,it delivers ultra-stable sodium storage up to 10,000 cycles at 5 A g^(−1) and potassium storage up to 5000 cycles at 2 A g^(−1).This study provides insights into constructing metal oxide-based carbon fiber network structures for high-performance electrochemical energy storage and conversion devices.

关键词： carbon fiber network heteroatom doping potassium-ion battery sodium-ion battery S-SnO2 quantum dot

Neurotrophins and neural stem cells in posttraumatic brain injury repair

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Animal Models and Experimental Medicine 2024年第1期7卷 12-23页

作者： Wenwen Guo ke liu Yinghua Wang Xu Ge Yifan Ma Jing Qin Caiqin Zhang Ya Zhao Changhong Shi Laboratory Animal Center Fourth Military Medical UniversityXi'anP.R.China Gansu University of Traditional Chinese Medicine LanzhouP.R.China Medical College of Yan'an University Yan'anP.R.China

Traumatic brain injury(TBI)is the main cause of disability,mental health disorder,and even death,with its incidence and social costs rising steadily.Although different treatment strategies have been developed and tested to mitigate neurological decline,a definitive cure for these conditions remains elusive.Studies have revealed that vari-ous neurotrophins represented by the brain-derived neurotrophic factor are the key regulators of neuroinflammation,apoptosis,blood-brain barrier permeability,neurite regeneration,and memory function.These factors are instrumental in alleviating neu-roinflammation and promoting neuroregeneration.In addition,neural stem cells(NSC)contribute to nerve repair through inherent neuroprotective and immunomodulatory properties,the release of neurotrophins,the activation of endogenous NSCs,and in-tercellular signaling.Notably,innovative research proposals are emerging to combine BDNF and NSCs,enabling them to synergistically complement and promote each other in facilitating injury repair and improving neuron differentiation after TBI.In this review,we summarize the mechanism of neurotrophins in promoting neurogen-esis and restoring neural function after TBI,comprehensively explore the potential therapeutic effects of various neurotrophins in basic research on TBI,and investigate their interaction with NSCs.This endeavor aims to provide a valuable insight into the clinical treatment and transformation of neurotrophins in TBI,thereby promoting the progress of TBI therapeutics.

关键词： mutual effect neural stem cells neurological function neurotrophins traumatic brain injury

Chiral transfer amidst one-dimensional linear polymers and twodimensional network covalent organic frameworks:Striking a fine balance between helicity and crystallinity

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Nano Research 2024年第6期17卷 5726-5734页

作者： Xinlin Zha Mengjuan Zuo Guilin Xu Zhong Yan Haining You Yi Xiong Ying liu Yingying Li Liyan Yang ke liu Mufang Li Tao Zhao Dong Wang College of Chemistry and Chemical Engineering Donghua UniversityShanghai 201620China key Laboratory of Textile Fiber and Products Ministry of EducationWuhan Textile UniversityWuhan 430200China

The current landscape of chiral covalent organic frameworks(COFs)predominantly centered on constructing asymmetric molecular-scale chirality,often introducing an inherent contradiction to the COF symmetry and limiting diversity.Herein,we overcome these challenges by achieving chiral transfer between one-dimensional(1D)imine linear polymers(LPs)and two-dimensional(2D)networkβ-ketoenamine COFs composed of achiral monomers.We successfully synthesize several 1D imine LPs with mesoscopic helical chirality,comprising achiral C2-symmetric terephthalaldehyde and diamine linkers in a chiral supramolecular transcription system.Leveraging the irreversible tautomerism mechanism within the linker replacement approach,terephthalaldehyde(TPA)units in these helical 1D LPs are substituted with C3-symmetric 1,3,5-triformylphloroglucinol(TP),yielding the corresponding 2D networkβ-ketoenamine COFs.Crystallinity and helicity of the resultantβ-ketoenamine COFs intimately hinge on reaction conditions,including the aldehyde stoichiometry of Tp and TPA,as well as the quantity and concentration of the catalyst employed.Under optimized conditions,the nucleation and growth were precisely governed,achieving a harmonious equilibrium of crystallinity and helicity within the generated 2D networkβ-ketoenamine COFs,even with covalent bond rupture,recombination,and topological transition(from[C2+C2]to[C3+C2]).Impressively,the ground state chirality inherent to helical 1D LPs seamlessly transfers to helical 2D networkβ-ketoenamine COFs.This study not only offers new perspectives on the development of chiral functional COFs,but also provides fresh insights into the precise control of COFs'microscopic morphology.

关键词： chiral covalent organic frameworks chiral transfer dimensional transformation helicity

Neoadjuvant nivolumab with or without platinum-doublet chemotherapy based on PD-L1 expression in resectable NSCLC(CTONG1804):a multicenter open-label phase II study

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Signal Transduction and Targeted Therapy 2024年第1期9卷 249-258页

作者： Si-Yang liu Song Dong Xue-Ning Yang Ri-Qiang Liao Ben-Yuan Jiang Qun Wang Xiao-Song Ben Gui-Bin Qiao Jun-Tao Lin Hong-Hong Yan Li-Xu Yan Qiang Nie Hai-Yan Tu Bin-Chao Wang Jin-Ji Yang Qing Zhou Hong-Rui Li ke liu Wendy Wu Si-Yang Maggie liu Wen-Zhao Zhong Yi-Long Wu Guangdong Lung Cancer Institute Guangdong Provincial Key Laboratory of Translational Medicine in Lung CancerGuangdong Provincial People’s Hospital(Guangdong Academy of Medical Sciences)Southern Medical UniversityGuangzhouChina Department of Thoracic Surgery Zhongshan HospitalFudan UniversityShanghaiChina Department of Thoracic Surgery Guangdong Provincial People’s Hospital(Guangdong Academy of Medical Sciences)Southern Medical UniversityGuangzhouChina Department of Pathology Guangdong Provincial People’s Hospital(Guangdong Academy of Medical Sciences)Southern Medical UniversityGuangzhouChina Fujian key Laboratory of Advanced Technology for Cancer Screening and Early Diagnosis FuzhouChina Berry Oncology Corporation FuzhouChina Chinese Thoracic Oncology Group(CTONG) GuangzhouChina Department of Hematology The First Affiliated HospitalJinan UniversityGuangzhouChina

This prospective multicenter phase II study evaluated the clinical efficacy of neoadjuvant nivolumab-exclusive(N)and nivolumab–chemotherapy(N/C)combinations based on PD-L1 expression.Eligible patients exhibited resectable clinical stage IIA–IIIB(AJCC 8th edition)NSCLC without EGFR/ALK alterations.Patients received either mono-nivolumab(N)or nivolumab+nabpaclitaxel+carboplatin(N/C)for three cycles based on PD-L1 expression.The primary endpoint was the major pathological response(MPR).key secondary endpoints included the pathologic complete response(pCR),objective response rate(ORR),and event-free survival(EFS).Baseline PD-L1 expression and perioperative circulating tumor DNA(ctDNA)status were correlated with pCR and EFS.Fifty-two patients were enrolled,with 46 undergoing surgeries.The MPR was 50.0%(26/52),with 25.0%(13/52)achieving pCR,and 16.7%and 66.7%for patients with PD-L1≥50%in N and N/C groups,respectively.Thirteen(25.0%)patients experienced grade 3 or higher immune-related adverse events during neoadjuvant treatment.Patients with post-neoadjuvant ctDNA negativity was more likely to have pCR(39.1%)compared with those remained positive(6.7%,odds ratio=6.14,95%CI 0.84-Inf,p=0.077).With a median follow-up of 25.1 months,the 18-month EFS rate was 64.8%(95%CI 51.9–81.0%).For patients with ctDNA–vs.ctDNA+,the 18m-EFS rate was 93.8%vs 47.3%(HR,0.15;95%CI 0.04,0.94;p=0.005).Immunochemotherapy may serve as an optimal neoadjuvant treatment even for patients with PD-L1 expression≥50%.ctDNA negativity following neoadjuvant treatment and surgery could help identify superior pathological and survival benefits,which requires further confirmation in a prospective clinical trial(NCT04015778).

关键词： chemotherapy NSCLC treatment

Bayesian Filtering for High-Dimensional State-Space Models With State Partition and Error Compensation

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IEEE/CAA Journal of Automatica Sinica 2024年第5期11卷 1239-1249页

作者： ke Li Shunyi Zhao Biao Huang Fei liu key Laboratory of Advanced Process Control for Light Industry(Ministry of Education) Institute of AutomationJiangnan UniversityWuxi 214122China Department of Chemical and Materials Engineering University of AlbertaEdmonton AB T6G 2G6Canada

In the era of exponential growth of data availability,the architecture of systems has a trend toward high dimensionality,and directly exploiting holistic information for state inference is not always computationally affordable.This paper proposes a novel Bayesian filtering algorithm that considers algorithmic computational cost and estimation accuracy for high-dimensional linear systems.The high-dimensional state vector is divided into several blocks to save computation resources by avoiding the calculation of error covariance with immense dimensions.After that,two sequential states are estimated simultaneously by introducing an auxiliary variable in the new probability space,mitigating the performance degradation caused by state segmentation.Moreover,the computational cost and error covariance of the proposed algorithm are analyzed analytically to show its distinct features compared with several existing methods.Simulation results illustrate that the proposed Bayesian filtering can maintain a higher estimation accuracy with reasonable computational cost when applied to high-dimensional linear systems.

关键词： filtering estimation error

NCAD v1.0: a database for non-coding variant annotation and interpretation

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Journal of Genetics and Genomics 2024年第2期51卷 230-242页

作者： Xiaoshu Feng Sihan liu ke Li Fengxiao Bu Huijun Yuan Institute of Rare Diseases West China HospitalSichuan UniversityChengduSichuan 610044China

The application of whole genome sequencing is expanding in clinical diagnostics across various genetic disorders, and the significance of non-coding variants in penetrant diseases is increasingly being demonstrated. Therefore, it is urgent to improve the diagnostic yield by exploring the pathogenic mechanisms of variants in non-coding regions. However, the interpretation of non-coding variants remains a significant challenge, due to the complex functional regulatory mechanisms of non-coding regions and the current limitations of available databases and tools. Hence, we develop the non-coding variant annotation database (NCAD, http://***/), encompassing comprehensive insights into 665,679,194 variants, regulatory elements, and element interaction details. Integrating data from 96 sources, spanning both GRCh37 and GRCh38 versions, NCAD v1.0 provides vital information to support the genetic diagnosis of non-coding variants, including allele frequencies of 12 diverse populations, with a particular focus on the population frequency information for 230,235,698 variants in 20,964 Chinese individuals. Moreover, it offers prediction scores for variant functionality, five categories of regulatory elements, and four types of non-coding RNAs. With its rich data and comprehensive coverage, NCAD serves as a valuable platform, empowering researchers and clinicians with profound insights into non-coding regulatory mechanisms while facilitating the interpretation of non-coding variants.

关键词： Non-coding variants Annotation Variant interpretation Database