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Individualized prediction of perineural invasion in colorectal cancer: development and validation of a radiomics prediction model

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Chinese Journal of Cancer Research 2018年第1期30卷 40-50页

作者： Yanqi Huang Lan He Di Dong Caiyun Yang Cuishan Liang Xin Chen Zelan Ma Xiaomei Huang Su Yao Changhong Liang Jie Tian Zaiyi Liu Department of Radiology Guangdong General Hospital Guangdong Academy of Medical Sciences School of medicine South China University of Technology Key Laboratory of molecular imaging Chinese Academy of Sciences Department of Radiology the Affiliated Guangzhou First People's Hospital Guangzhou Medical University Department of Pathology Guangdong General Hospital Guangdong Academy of Medical Sciences

Objective： To develop and validate a radiomics prediction model for individualized prediction of perineural invasion（PNI） in colorectal cancer（CRC）.Methods： After computed tomography（CT） radiomics features extraction, a radiomics signature was constructed in derivation cohort（346 CRC patients）. A prediction model was developed to integrate the radiomics signature and clinical candidate predictors [age, sex, tumor location, and carcinoembryonic antigen（CEA） level]. Apparent prediction performance was assessed. After internal validation, independent temporal validation（separate from the cohort used to build the model） was then conducted in 217 CRC patients. The final model was converted to an easy-to-use ***： The developed radiomics nomogram that integrated the radiomics signature and CEA level showed good calibration and discrimination performance [Harrell＇s concordance index（c-index）： 0.817; 95% confidence interval（95% CI）： 0.811–0.823]. Application of the nomogram in validation cohort gave a comparable calibration and discrimination（c-index： 0.803; 95% CI： 0.794–0.812）.Conclusions： Integrating the radiomics signature and CEA level into a radiomics prediction model enables easy and effective risk assessment of PNI in CRC. This stratification of patients according to their PNI status may provide a basis for individualized auxiliary treatment.

关键词： Colorectal cancer perineural invasion prediction model radiomics nomogram

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Structure-activity relationship of pyrazol-4-ylpyridine derivatives and identification of a radiofluorinated probe for imaging the muscarinic acetylcholine receptor M4

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Acta Pharmaceutica Sinica B 2023年第1期13卷 213-226页

作者： Ahmed Haider Xiaoyun Deng Olivia Mastromihalis Stefanie K.Pfister Troels E.Jeppesen Zhiwei Xiao Vi Pham Shaofa Sun Jian Rong Chunyu Zhao Jiahui Chen Yinlong Li Theresa R.Connors April T.Davenport James B.Daunais Vahid Hosseini Wenqing Ran Arthur Christopoulos Lu Wang Celine Valant Steven H.Liang Department of Radiology Division of Nuclear Medicine and Molecular Imaging Massachusetts General Hospital and Harvard Medical SchoolBostonMA 02114USA Department of nuclear medicine Tongji HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhan 430030China Drug Discovery Biology Monash Institute of Pharmaceutical SciencesMonash UniversityParkvilleVIC 3052Australia Neuromedicines Discovery Centre Monash Institute of Pharmaceutical SciencesMonash UniversityParkvilleVIC 3052Australia Hubei Collaborative Innovation Centre for Non-power nuclear Technology College of Nuclear Technology&Chemistry and BiologyHubei University of Science and TechnologyXianning 437100China Department of Neurology Massachusetts General HospitalHarvard Medical SchoolBostonMA 02114USA Department of Physiology and Pharmacology Wake Forest School of MedicineWinston SalemNC 27157USA Terasaki Institute for Biomedical Innovation(TIBI) Los AngelesCA 90024USA Center of Cyclotron and PET Radiopharmaceuticals Department of Nuclear Medicine and PET/CT-MRI Centerthe First Affiliated Hospital of Jinan UniversityGuangzhou 510630China

There is an accumulating body of evidence implicating the muscarinic acetylcholine receptor4(M4)in schizophrenia and dementia with Lewy bodies,however,a clinically validated M4positron emission tomography(PET)radioligand is currently *** such,the aim of this study was to develop a suitable M4PET ligand that allows the non-invasive visualization of M4in the ***-activity relationship studies of pyrazol-4-yl-pyridine derivates led to the discovery of target compound 12—a subtype-selective positive allosteric modulator(PAM).The radiofluorinated analogue,[18F]12,was synthesized in 28±10%radiochemical yield,>37 GBq/μmol and an excellent radiochemical purity>99%.Initial in vitro autoradiograms on rodent brain sections were performed in the absence of carbachol and showed moderate specificity as well as a low selectivity of[18F]12 for the M4-rich ***,in the presence of carbachol,a significant increase in tracer binding was observed in the rat striatum,which was reduced by>60%under blocking conditions,thus indicating that orthosteric ligand interaction is required for efficient binding o f[18F]12 to the allosteric ***,however,the presence of carbachol was not required for high specific binding in the non-human primate(NHP)and human striatum,and did not further improve the specificity and selectivity of[18F]12 in higher *** results pointed towards significant species-differences and paved the way for a preliminary PET study in NHP,where peak brain uptake of[18F]12 was found in the putamen and temporal *** conclusion,we report on the identification and preclinical development of the first radiofluorinated M4PET radioligand with promising *** availability of a clinically validated M4PET radioligand harbors potential to facilitate drug development and provide a useful diagnostic tool for non-invasive imaging.

关键词： Muscarinicacetylcholine receptor Positronemission tomography Neuroimaging Neuropharmacology Neurological disorders

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AS1411 aptamer-conjugated Gd2O3：Eu nanoparticles for target-specific computed tomography/magnetic resonance/fluorescence molecular imaging

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Nano Research 2014年第5期7卷 658-669页

作者： Tsungrong Kuo Weiyun Lai Chenghung Li Yanjhan Wun Huancheng Chang Jinnshiun Chen Panchyr Yang Chiachun Chen Department of Chemistry 'National Taiwan Normal University' Taipei 116 Taiwan China Institute of Atomic and molecular Science 'Academia Sinica' Taipei 106 Taiwan China molecular medicine program Taiwan International Graduate Program Institute of Biomedical Sciences 'Academia Sinica' Taipei 115 Taiwan China Institute of Biochemistry and molecular Biology School of Life Sciences 'National Yang-Ming University' Taipei 112 Taiwan China Division of Colorectal Surgery Chang Gung Memorial Hospital Chang Gung University Taoyuan 333 Taiwan China College of medicine 'National Taiwan University' Taipei 106 Taiwan China

Europium-doped gadolinium oxide （Gd2O3：Eu） nanoparticles have been synthesized, and then their surfaces have been conjugated with nucleolin- targeted AS1411 aptamer to form functionalized target-specific Gd2OB：EU nanoparticles （A-GdO：Eu nanoparticles）. The A-GdO：Eu nanoparticles present strong fluorescence in the visible range, high magnetic susceptibility, X-ray attenuation and good biocompatibility. The A-GdO：Eu nanoparticles have been applied to test molecular expression of nucleolin highly expressed CL1-5 lung cancer cells under a confocal microscope. Fluorescence imaging clearly reveals that the nanoparticles can be applied as fluorescent tags for cancer-targeting molecular imaging. Furthermore, taking together their excellent T1 contrast and strong computed tomography （CT） signal, the A-GdO：Eu nanoparticles demonstrate a great capability for use as a dual modality contrast agent for CT and magnetic resonance （MR） molecular imaging. Animal experiments also show that the A-GdO：Eu nanoparticles are able to contrast the tissues of BALB/c mice using CT modality. Moreover, the obvious red fluorescence of A-GdO：Eu nanoparticles can be visualized in a tumor by the naked eye. Overall, our results demonstrate that the A-GdO：Eu nanoparticles can not only serve as new medical contrast agents but also as intraoperative fluorescence imaging probes for guided surgery in the near future.

关键词： aptamer contrast agent Gd2O3 nanoparticles molecular imaging nanoparticles synthesis

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Metabolic basis of solute carrier transporters in treatment of type 2 diabetes mellitus

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Acta Pharmaceutica Sinica B 2024年第2期14卷 437-454页

作者： Jiamei Le Yilong Chen Wei Yang Ligong Chen Jianping Ye Shanghai Key Laboratory of molecular imaging Zhoupu HospitalShanghai University of Medicine and Health SciencesShanghai 201318China School of Health Science and Engineering University of Shanghai for Science and TechnologyShanghai 200093China Metabolic Disease Research Center Zhengzhou Central Hospital Affiliated to Zhengzhou UniversityZhengzhou 450007China School of Pharmaceutical sciences Tsinghua UniversityBeijing 100084China Research Center for Basic medicine Academy of Medical SciencesZhengzhou UniversityZhengzhou 450052China

Solute carriers(SLCs) constitute the largest superfamily of membrane transporter *** transporters, present in various SLC families, play a vital role in energy metabolism by facilitating the transport of diverse substances, including glucose, fatty acids, amino acids, nucleotides, and *** actively participate in the regulation of glucose metabolism at various steps, such as glucose uptake(e.g., SLC2A4/GLUT4), glucose reabsorption(e.g., SLC5A2/SGLT2), thermogenesis(e.g., SLC25A7/UCP-1), and ATP production(e.g., SLC25A4/ANT1 and SLC25A5/ANT2). The activities of these transporters contribute to the pathogenesis of type 2 diabetes mellitus(T2DM). Notably, SLC5A2 has emerged as a valid drug target for T2DM due to its role in renal glucose reabsorption, leading to groundbreaking advancements in diabetes drug discovery. Alongside SLC5A2, multiple families of SLC transporters involved in the regulation of glucose homeostasis hold potential applications for T2DM therapy. SLCs also impact drug metabolism of diabetic medicines through gene polymorphisms, such as rosiglitazone(SLCO1B1/OATP1B1) and metformin(SLC22A1-3/OCT1-3 and SLC47A1, 2/MATE1, 2). By consolidating insights into the biological activities and clinical relevance of SLC transporters in T2DM, this review offers a comprehensive update on their roles in controlling glucose metabolism as potential drug targets.

关键词： Solute carriers(SLCs) Energ ymetabolism ATP production Type 2 diabetes mellitus(T2DM) Glucose homeostasis Polymorphisms

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Manganese therapy for dyslipidemia and plaque reversal in murine models

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Life Metabolism 2023年第6期2卷 82-87页

作者： Yawei Wang Xin Feng Wenjing Zhou Runze Huang Yating Hu Hui Hui Jie Tian Xiao Wang Xiao-Wei Chen State Key Laboratory of Membrane Biology Peking UniversityBeijing 100871China Institute of molecular medicine College of Future TechnologyPeking UniversityBeijing 100871China PKU-THU Joint Center for Life sciences Peking UniversityBeijing 100871China CAS Key Laboratory of molecular imaging Institute of AutomationChinese Academy of SciencesBeijing 100190China Beijing Key Laboratory of molecular imaging Beijing 100190China School of Artificial Intelligence University of Chinese Academy of SciencesBeijing 100080China

Precise control of circulating lipid levels is vital in both health and *** recently uncovered that bulk lipids,transported by lipoproteins,enter the circulation initially via the coat protein complex II(COPII)in a condensation-dependent *** manganese,acting as a signaling messenger,selectively controls COPII condensation to regulate lipid homeostasis in ***,we present evidence for a manganese-based therapy in murine models of hypolipidemia and hyperlipidemia.

关键词： manganese homeostasis initially

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Arginine-solubilized lipoic acid-induced β-sheets of silkfibroin-strengthened hydrogel for postoperative rehabilitation ofbreast cancer

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Bioactive Materials 2024年第10期40卷 667-682页

作者： Zhuodan Zhang Yi Xia Xinyi Li Qian Zhang Yuanhao Wu Chunyan Cui Jianfeng Liu Wenguang Liu School of Material Science and Engineering Tianjin Key Laboratory of Composite and Functional MaterialsTianjin UniversityTianjin300352China State Key Laboratory of Advanced Medical Materials and Devices Tianjin Key Laboratory of Radiation Medicine and Molecular Nuclear MedicineKey Laboratory of Radiopharmacokinetics for Innovative DrugsTianjin Institutes of Health ScienceInstitute of Radiation MedicineChinese Academy of Medical Sciences&Peking Union Medical CollegeTianjin300192China State Key Laboratory of molecular Engineering of Polymers(Fudan University) China

Breast cancer is the most common cancer among women worldwide, and adjuvant radiotherapy (RT) followingtumor removal is one of the most commonly used treatments for breast cancer. However, the high risk of tumorrecurrence and inevitable radiation skin injury after RT remain fatal problems, seriously challenging the patient’spostoperative rehabilitation. Herein, a multifunctional poly (lipoic acid)-based hydrogel is constructed throughone-step heating the mixture of α-lipoic acid (LA)/arginine (Arg)/silk fibroin (SF), without introducing any nonnaturalmolecules. The multiple synergistic interactions among LA, Arg, and SF not only enhance the solubilizationof LA in aqueous systems but also stabilize poly(lipoic acid) through strong salt bridge hydrogen bondsand ionic hydrogen bonds. Intriguingly, the LA-based surfactant induced β-sheet transformation of SF can furthermodulate the bulk strength of the hydrogel. Regulating the content of LA in hydrogels not only allows efficientcontrol of hydrogel bioactivity but also enables the evolution of hydrogels from injectable forms to adhesivepatches. Based on the different biological activities and forms of hydrogels, they can be implanted internally orapplied externally on the mice’s skin, achieving simultaneous prevention of tumor recurrence post-surgery andassistance in treating radiation-induced skin damage after radiotherapy.

关键词： α-lipoic acid Adhesive hydrogel Injectable hydrogel Tumor inhibition Wound healing

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Triggering Receptor Expressed on Myeloid Cells 2 Alleviated Sevoflurane-Induced Developmental Neurotoxicity via Microglial Pruning of Dendritic Spines in the CA1 Region of the Hippocampus

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Neuroscience Bulletin 2024年第9期40卷 1215-1229页

作者： Li Deng Shao-Yong Song Wei-Ming Zhao Xiao-Wen Meng Hong Liu Qing Zheng Ke Peng Fu-Hai Ji Department of Anaesthesiology The First Affiliated Hospital of Soochow UniversitySuzhou215006China Institute of Anaesthesiology Soochow UniversitySuzhou215006China Department of Anaesthesiology Dushu Lake Hospital Affiliated of Soochow UniversitySuzhou215000China Department of Anaesthesiology and Pain medicine University of California Davis HealthSacramentoCAUSA Center for molecular imaging and nuclear medicine Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher EducationState Key Laboratory of Radiation Medicine and ProtectionSchool for Radiological and Interdisciplinary Sciences(RAD-X)Suzhou Medical College of Soochow UniversitySuzhou215006China

Sevoflurane induces developmental neurotoxicity in mice;however,the underlying mechanisms remain *** receptor expressed on myeloid cells 2(TREM2)is essential for microglia-mediated synaptic refinement during the early stages of brain *** explored the effects of TREM2 on dendritic spine pruning during sevoflurane-induced developmental neurotoxicity in *** were anaesthetized with sevoflurane on postnatal days 6,8,and *** performance was assessed using the open field test and Morris water maze *** knockdown of TREM2 and overexpression of TREM2 by stereotaxic injection were used for mechanistic *** blotting,immunofluorescence,electron microscopy,three-dimensional reconstruction,Golgi staining,and whole-cell patch-clamp recordings were *** exposures upregulated the protein expression of TREM2,increased microglia-mediated pruning of dendritic spines,and reduced synaptic multiplicity and excitability of CA1 ***2 genetic knockdown significantly decreased dendritic spine pruning,and partially aggravated neuronal morphological abnormalities and cognitive impairments in sevoflurane-treated *** contrast,TREM2 overexpression enhanced microglia-mediated pruning of dendritic spines and rescued neuronal morphological abnormalities and cognitive ***2 exerts a protective role against neurocognitive impairments in mice after neonatal exposures to sevoflurane by enhancing microglia-mediated pruning of dendritic spines in CA1 *** provides a potential therapeutic target in the prevention of sevoflurane-induced developmental neurotoxicity.

关键词： CA1 neurons Dendritic spines Developmental neurotoxicity Microglia Sevoflurane TREM2

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SUMO-1 modification of FEN1 facilitates its interaction with Rad9-Radl-Husl to counteract DNA replication stress

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Journal of molecular Cell Biology 2018年第5期10卷 460-474页

作者： Xiaoli Xu Rongyi Shi Li Zheng Zhigang Guo Liangyan Wang Mian Zhou Ye Zhao Bing Tian Khue Truong Yuan Chen Binghui Shen Yuejin Hua Hong Xu Institute of nuclear-Agricultural sciences Zhejiang University Hangzhou 310029 China Department of Cancer Genetics and Epigenetics City of Hope National Medical Center and Beckman Research Institute Duarte CA 91010 USA Jiangsu Key Laboratory for molecular and Medical Biotechnology and College of Life sciences Nanjing Normal University Nanjing 210046 China Department of molecular medicine City of Hope National Medical Center and Beckman Research Institute Duarte CA 91010 USA

Human flap endonuclease 1 （FEN1） is a structure-specific, multi-functional endonuclease essential for DNA replication and repair. We and others have shown that during DNA replication, FEN1 processes Okazaki fragments via its interaction with the proliferating cell nuclear antigen （PCNA）. Alternatively, in response to DNA damage, FEN1 interacts with the PCNA-like Radg-Radl-Husl complex instead of PCNA to engage in DNA repair activities, such as homology-directed repair of stalled DNA replication forks. However, it is unclear how FEN1 is able to switch between these interactions and its roles in DNA replication and DNA repair. Here, we report that FEN1 undergoes SUMOylation by SUMO-1 in response to DNA replication fork-staUing agents, such as UV irradiation, hydroxyurea, and mitomycin C. This DNA damage-induced SUMO-1 modification promotes the interaction of FEN1 with the Radg-Rad1-Husl complex. Furthermore, we found that FEN1 mutations that prevent its SUMO-1 modification also impair its ability to interact with HUS1 and to rescue stalled replication forks. These impairments lead to the accumulation of DNA damage and heightened sensitivity to fork-staUing agents. Altogether, our findings suggest an important role of the SUMO-1 modification of FEN1 in regulating its roles in DNA replication and repair.

关键词： flap endonuclease 1 Rad9-Rad1-Hus1 complex replication stress SUMOylation

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Self-assembled multifunctional DNA nanoflowers for the circumvention of multidrug resistance in targeted anticancer drug delivery

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Nano Research 2015年第11期8卷 3447-3460页

作者： Lei Mei Guizhi Zhu Liping Qiu Cuichen Wu Huapei Chen Hao Liang Sena Cansiz Yifan Lv Xiaobing Zhang Weihong Tan molecular sciences and Biomedicine Laboratory State Key Laboratory for Chemo/Biosensing and Chemometrics College of Chemistry and Chemical Engineering College of Biology Collaborative Innovation Center for Chemistry and Molecular Medicine Hunan University Changsha 410082 China Departments of Chemistry Physiology and Functional Genomics Center for Research at the Bio/Nano Interface Shands Cancer Center UF Genetics Institute and McKnight Brain Institute University of Florida Gainesville FL 32611-7200 USA Laboratory of molecular imaging and Nanomedicine National Institute of Biomedical Imaging and Bioengineering National Institutes of Health Bethesda MD 20892 USA

Cancer chemotherapy has been limited by its side effects and multidrug resistance （MDR）, the latter of which is partially caused by drug efflux from cancer cells. Thus, targeted drug delivery systems that can circumvent MDR are needed. Here, we report multifunctional DNA nanoflowers （NFs） for targeted drug delivery to both chemosensitive and MDR cancer cells that circumvented MDR in both leukemia and breast cancer cell models. NFs are self-assembled via potential co-precipitation of DNA and magnesium pyrophosphate generated by rolling circle replication, during which NFs are incorporated using aptamers for specific cancer cell recognition, fluorophores for bioimaging, and doxorubicin （Dox）- binding DNA for drug delivery. NF sizes are tunable （down to N200 nm in diameter）, and the densely packed drug-binding motifs and porous intrastructures endow NFs with a high drug-loading capacity （71.4%, wt/wt）. Although the Dox- loaded NFs （NF-Dox） are stable at physiological pH, drug release is facilitated under acidic or basic conditions. NFs deliver Dox into target chemosensitive and MDR cancer cells, preventing drug efflux and enhancing drug retention in MDR cells. NF-Dox induces potent cytotoxicity in both target chemosensitive cells and MDR cells, but not in nontarget cells, thus concurrently circumventing MDR and reducing side effects. Overall, these NFs are promising tools for circumventing MDR in targeted cancer therapy.

关键词： aptamer rolling circle replication self-assembly DNA nanotechnology multidrug resistance targeted cancer therapy

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A multifunctional nanotheranostic agent potentiates erlotinib to EGFR wild-type non-small cell lung cancer

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Bioactive Materials 2022年第7期7卷 312-323页

作者： Duo Wang Jun Zhou Weimin Fang Cuiqing Huang Zerong Chen Meng Fan Ming-Rong Zhang Zeyu Xiao Kuan Hu Liangping Luo Medical imaging Center The First Affiliated Hospital of Jinan UniversityGuangzhou510632PR China The Guangzhou Key Laboratory of molecular and Functional imaging for Clinical Translation Jinan UniversityGuangzhou510632PR China Department of Advanced nuclear medicine sciences Institute of Quantum Medical ScienceNational Institutes for Quantum and Radiological Science and TechnologyChiba263-8555Japan Center for Nanomedicine and Department of Anesthesiology Brigham and Women’s HospitalHarvard Medical SchoolBostonMA02115USA

Epidermal growth factor receptor(EGFR)tyrosine kinase inhibitors(TKI),such as Erlotinib,have demonstrated remarkable efficacy in the treatment of non-small cell lung cancer(NSCLC)patients with mutated ***,the efficacy of EGFR-TKIs in wild-type(wt)EGFR tumours has been shown to be *** that can sensitize Erlotinib to EGFR wild-type NSCLC remain ***,we developed a multifunctional superparamagnetic nanotheranostic agent as a novel strategy to potentiate Erlotinib to EGFR-wt *** results demonstrate that the nanoparticles can co-escort Erlotinib and a vascular epithermal growth factor(VEGF)inhibitor,Bevacizumab(Bev),to EGFR-wt *** nanotheranostic agent exhibits remarkable effects as an inhibitor of EGFR-wt tumour ***,Bev normalizes the tumour embedded vessels,further promoting the therapeutic efficacy of *** addition,the tumour engagement of the nanoparticles and the vascular normalization could be tracked by magnetic resonance imaging(MRI).Collectively,our study,for the first time,demonstrated that elaborated nanoparticles could be employed as a robust tool to potentiate Erlotinib to EGFR-wt NSCLC,paving the way for imaging-guided nanotheranostics for refractory NSCLCs expressing EGFR wild-type genes.

关键词： Non-small cell lung cancer EGFR wild-Type Superparamagnetic iron oxide Erlotinib Bevacizumab Tumour vascular normalization

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