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Progress in clinical diagnosis and treatment of colorectal cancer with rare genetic variants

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Cancer Biology & Medicine 2024年第6期21卷 473-483页

作者： Shuyi Chen Jing Gu Kaichun Wu Xiaodi zhao yuanyuan Lu State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers and National Clinical Research Center for Digestive Diseases Xijing Hospital of Digestive Diseases Fourth Military Medical University School of Basic Medical Sciences Fourth Military Medical University

Targeted therapy is crucial for advanced colorectal cancer(CRC) positive for genetic drivers. With advances in deep sequencing technology and new targeted drugs, existing standard molecular pathological detection systems and therapeutic strategies can no longer meet the requirements for careful management of patients with advanced CRC. Thus, rare genetic variations require diagnosis and targeted therapy in clinical practice. Rare gene mutations, amplifications, and rearrangements are usually associated with poor prognosis and poor response to conventional therapy. This review summarizes the clinical diagnosis and treatment of rare genetic variations, in genes including erb-b2 receptor tyrosine kinase 2(ERBB2), B-Raf proto-oncogene, serine/threonine kinase(BRAF), ALK receptor tyrosine kinase/ROS proto-oncogene 1, receptor tyrosine kinase(ALK/ROS1), neurotrophic receptor tyrosine kinases(NTRKs), ret proto-oncogene(RET), fibroblast growth factor receptor 2(FGFR2), and epidermal growth factor receptor(EGFR), to enhance understanding and identify more accurate personalized treatments for patients with rare genetic variations.

关键词： Genetic variation gene amplification gene mutation gene rearrangement targeted therapy

Atherosis-associated lnc_000048 activates PKR to enhance STAT1-mediated polarization of THP-1 macrophages to M1 phenotype

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Neural Regeneration Research 2024年第11期19卷 2488-2498页

作者： yuanyuan Ding Yu Sun Hongyan Wang Hongqin zhao Ruihua Yin Meng Zhang Xudong Pan Xiaoyan Zhu Department of Neurology The Affiliated Hospital of Qingdao UniversityQingdaoShandong ProvinceChina Qingdao Cadre Health Care Service Center The Affiliated Hospital of Qingdao UniversityQingdaoShandong ProvinceChina Department of Critical Care Medicine The Affiliated Hospital of Qingdao UniversityQingdaoShandong ProvinceChina

Our previous study has demonstrated that lnc_000048 is upregulated in large-artery atherosclerotic stroke and promotes atherosclerosis in ApoE^(-/-)mice.However,little is known about the role of lnc_000048 in classically activated macrophage(M1)polarization.In this study,we established THP-1-derived testing state macrophages(M0),M1 macrophages,and alternately activated macrophages(M2).Real-time fluorescence quantitative PCR was used to verify the expression of marker genes and the expression of lnc_000048 in macrophages.Flow cytometry was used to detect phenotypic proteins(CD11b,CD38,CD80).We generated cell lines with lentivirus-mediated upregulation or downregulation of lnc_000048.Flow cytometry,western blot,and real-time fluorescence quantitative PCR results showed that down-regulation of lnc_000048 reduced M1 macrophage polarization and the inflammation response,while over-expression of lnc_000048 led to the opposite effect.Western blot results indicated that lnc_000048 enhanced the activation of the STAT1 pathway and mediated the M1 macrophage polarization.Moreover,catRAPID prediction,RNA-pull down,and mass spectrometry were used to identify and screen the protein kinase RNA-activated(PKR),then catRAPID and RPIseq were used to predict the binding ability of lnc_000048 to PKR.Immunofluorescence(IF)-RNA fluorescence in situ hybridization(FISH)double labeling was performed to verify the subcellular colocalization of lnc_000048 and PKR in the cytoplasm of M1 macrophage.We speculate that lnc_000048 may form stem-loop structure-specific binding and activate PKR by inducing its phosphorylation,leading to activation of STAT1 phosphorylation and thereby enhancing STAT1 pathway-mediated polarization of THP-1 macrophages to M1 and inflammatory factor expression.Taken together,these results reveal that the lnc_000048/PKR/STAT1 axis plays a crucial role in the polarization of M1 macrophages and may be a novel therapeutic target for atherosclerosis alleviation in stroke.

关键词： atherosclerosis inflammation lnc_000048 lncRNA macrophage polarization protein kinase RNA-activated(PKR) STAT1

Directional amine-based solvent extraction for simultaneous enhanced water recovery,salt separation and effective descaling from hypersaline brines

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Frontiers of Environmental Science & Engineering 2024年第3期18卷 83-92页

作者： Yuyao Zhang Litao Jia Jin zhao Xuming Liu Shuyu Dong Chuanyang Liu yuanyuan Cui Shougang Research Institute of Technology Beijing 100043China Research Center of Environmental Technology in Water Pollution Source Identification and Precise Supervision School of EnvironmentTsinghua UniversityBeijing 100084China

The feasibility of simultaneous water recovery,salt separation and effective descaling of hypersaline brine was investigated by diisopropylamine(DIPA)-based directional solvent extraction(DSE),using diluted/concentrated seawater with initial saline concentration range of 12–237 g/L at extraction temperatures of 5 and 15℃,respectively.The water recovery shows an obvious boundary at saline concentration of 115 g/L under dual effect of specific water extraction efficiency and extraction cycles.High Cl^(–) ion concentration in product water is in sharp contrast to the nearly complete removal of SO_(4)^(2–)and hardness ions,indicating that DIPA-based DSE process indeed achieved efficient separation and purification of Cl^(–) ion from hypersaline brines.Especially,the radical precipitation of Mg^(2+)and Ca^(2+)ions in form of Mg(OH)_(2)and CaCO_(3)demonstrates effective descaling potential,although it leads to more DIPA residues in dewatered raffinate than product water.Moreover,an exponential correlation between the Cl^(–) removal efficiency and specific water extraction efficiency further reveals the intrinsic relationship of water extraction process and transfer of Cl^(–) ion to the product water.Overall,the study provides a novel approach for integrating the water recovery and separation of Cl^(–) ion from ultra-high-salinity brines with radical precipitation of Mg^(2+)and Ca^(2+) ions in one step.

关键词： Hypersaline brines Directional solvent extraction Salt separation Ca^(2+)and Mg^(2+)descaling

Highly sensitive flexible strain sensor based on the two-dimensional semiconductor tellurium with a negative gauge factor

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Science China(Information Sciences) 2024年第7期67卷 295-304页

作者： Jiarui HE Yusong QU Shengyao CHEN Cong WANG Lena DU Xiaoshan DU yuanyuan ZHENG Guozhong zhao He TIAN College of Mathematics and Physics Beijing University of Chemical Technology School of Integrated Circuits Tsinghua University Beijing China & The Beijing National Research Center for Information Science and Technology (BNRist)Tsinghua University CAS Center for Excellence in Nanoscience National Center for Nanoscience and Technology &University of Chinese Academy of Sciences Beijing Key Lab of Terahertz Spectroscopy and Imaging Key Lab of Terahertz OptoelectronicsMinistry of Education Department of Physics Capital Normal University

Research on flexible strain sensors has advanced rapidly in recent years, with particular attention being devoted to two-dimensional(2D) semiconductor materials owing to their exceptional mechanical and electrical properties that are conducive to sophisticated sensing performance. However, resistive strain sensors based on 2D semiconductor materials typically exhibit positive gauge factors(GF), while materials for strain sensors with a negative GF remain elusive. We have identified a trend of reduction in the band gap of the emerging 2D semiconductor material tellurium(Te) under strain in simulations reported in past research,and have observed a negative GF in the Te-based strain sensor. In this study, we combined Te with a flexible polyethylene terephthalate(PET) substrate to manufacture a flexible strain sensor with a significantly negative GF. The results of tests revealed that the Te-based strain sensor achieved an impressive maximum sensitivity of-139.7 within a small range of bending-induced strain(< 1%). Furthermore, it exhibited excellent linearity and good cyclic stability, and was successfully applied to monitor limb movements. The work here verifies the significant potential for the use of Te-based strain sensors in next-generation flexible electronics.

关键词： 2D semiconductor materials 2D tellurium flexibleelectronics strain sensors negative gauge factor high sensitivity

QL1706 (anti-PD-1 IgG4/CTLA-4 antibody) plus chemotherapy with or without bevacizumab in advanced non-small cell lung cancer: a multi-cohort, phase II study

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Signal Transduction and Targeted Therapy 2024年第2期9卷 797-806页

作者： Yan Huang Yunpeng Yang yuanyuan zhao Hongyun zhao Ningning Zhou Yaxiong Zhang Likun Chen Ting Zhou Gang Chen Ting Wu Lu Lu Shilin Xue Xiaoyan Kang Li Zhang Wenfeng Fang Department of Medical Oncology Sun Yat-sen University Cancer CenterState Key Laboratory of Oncology in South ChinaCollaborative Innovation Center for Cancer MedicineNo.651 Dongfeng East RoadGuangzhouGuangdong 510060China Department of Medicine Qilu Pharmaceutical Co.Ltd.JinanChina

First-line chemoimmunotherapy(with or without bevacizumab)has improved outcomes in advanced non-small cell lung cancer(NSCLC).Here,this open-label,multi-cohort phase II study(NCT05329025)was done to investigate the safety and efficacy of QL1706(a single bifunctional MabPair product against PD-1 and CTLA-4)and chemotherapy with or without bevacizumab in this population.Patients were enrolled into five different cohorts based on genotype(cohorts 1-4,epidermal growth factor receptor[EGFR]wild-type;cohort 5,EGFR-mutant and progressed on EGFR-tyrosine kinase inhibitors[TKIs]).Between June 11,2021 and December 29,2021,91 patients were enrolled.Most frequent treatment-related adverse events(TRAEs)included decreased appetite(60[65.9%]),anemia(60[65.9%]),infusion-related reactions(48[52.7%]),and pruritus(44[48.4%]).Grade≥3 TRAEs occurred in 30(33.0%)patients.Twenty-seven(45%)patients with wild-type EGFR achieved partial response(PR)(objective response rate[ORR]=45%)and had a median progression-free survival(mPFS)of 6.8 months(95%CI:5.2-9.7).For 31 patients harboring mutated EGFR,17(54.8%)achieved PR(ORR=54.8%),with an mPFS of 8.5 months(95%CI:5.72-not evaluable).Overall,QL1706 plus chemotherapy,regardless of having bevacizumab,was generally tolerable and had promising antitumor activity for EGFR wild-type advanced NSCLC in first-line setting.Moreover,QL1706 plus chemotherapy and bevacizumab showed favorable antitumor activity for patients who had EGFR mutated NSCLC but failed in TKI therapy,demonstrating a potential for treating this population.

关键词： bevacizumab chemotherapy phase

Single-cell mass spectrometry studies of drug metabolism heterogeneity and primary resistance to gefitinib in non-small cell lung cancer cells

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Chinese Chemical Letters 2024年第2期35卷 436-440页

作者： Guizhen Zhu Yaoyao zhao Wenmei Zhang yuanyuan Wu Yuanxing Liu Guangsheng Guo Xiayan Wang Zhihong Liu Center of Excellence for Environmental Safety and Biological Effects Beijing Key Laboratory for Green Catalysis and SeparationDepartment of ChemistryBeijing University of TechnologyBeijing 100124China Minzu University of China Beijing 100081China Key Laboratory for the Synthesis and Application of Organic Functional Molecules College of Health Science and EngineeringHubei UniversityWuhan 430062China

Patients with epidermal growth factor receptor(EGFR)wild-type non-small cell lung cancer(NSCLC)often show primary resistance to gefitinib therapy.It is thus necessary to study the metabolism of gefitinib in NSCLC cells to comprehensively reveal the reasons for the primary resistance of tumors.Herein,we develop a platform for studying drug metabolism heterogeneity based on single-cell mass spectrometry(sDMH-scMS)by integrating living-cell electrolaunching ionization MS(ILCEI-MS)and high-performance liquid chromatography-MS(HPLC-MS)analysis,and the primary resistance of NSCLC cells to gefitinib was studied using this platform.The ILCEI-MS analysis showed that approximately 11.9%of NSCLC single cells contained the gefitinib metabolite M11;HPLC-MS detection diluted the intensity of M11 in subpopulations and concealed the heterogeneity of drug metabolism in tumor single cells.The intensity of gefitinib in EGFR wild-type A549 cells was markedly lower than in mutant PC9 cells,and the intensity of gefitinib metabolites was significantly higher than in PC9 cells,suggesting that the primary resistance of NSCLC cells is related to gefitinib metabolism.Moreover,the combination of gefitinib and the drug-metabolizing enzyme inhibitorα-naphthoflavone was shown to overcome the primary resistance of the NSCLC cells.Overall,the results of this study are expected to be applicable for clinical drug resistance diagnosis and treatment at the single-cell level.

关键词： Single-cell mass spectrometry Drug metabolism Non-small cell lung cancer Gefitinib Primary resistance

Flexible bidirectional self-powered photodetector with significantly reduced volume and accelerated response speed based on hydrogel and lift-off GaN-based nanowires

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Fundamental Research 2024年第2期4卷 369-378页

作者： Min Jiang Yukun zhao Penghui Zheng Jianya Zhang Wenxian Yang Min Zhou yuanyuan Wu Renjun Pei Shulong Lu Key Lab of Nanodevices and Applications Suzhou Institute of Nano-Tech and Nano-Bionics(SINANO)Chinese Academy of Sciences(CAS)Suzhou 215123China School of Nano-Tech and Nano-Bionics University of Science and Technology of ChinaHefei 230026China CAS Key Laboratory of Nano-Bio Interface Suzhou Institute of Nano-Tech and Nano-BionicsChinese Academy of SciencesSuzhou 215123China Nanchang Research Institute Suzhou Institute of Nano-Tech and Nano-BionicsChinese Academy of SciencesNanchang 330200China

Due to the wide range of potential applications for next-generation multi-functional devices,the flexible selfpowered photodetector(PD)with polarity-switchable behavior is essential but very challenging to be realized.Herein,a wearable bidirectional self-powered PD based on detached(Al,Ga)N and(In,Ga)N nanowires has been proposed and demonstrated successfully.Arising from the photovoltage-competing dynamics across(Al,Ga)N and(In,Ga)N nanowire photoelectrodes,such PD can generate the positive(33.3 mA W−1)and negative(-0.019 mA W−1)photo-responsivity under ultraviolet(UV)and visible illumination,respectively,leading to the bidirectional photocurrent behavior.Thanks to the introduction of quasi solid-state hydrogel,the PD can work without the liquid-electrolyte,thus remarkably reducing the volume from about 482 cm3 to only 0.18 cm3.Furthermore,the use of hydrogel is found to enhance response speed in the UV range by reducing the response time for more than 95%,which is mainly attributed to the increased open circuit potential and reduced ion transport distance.As the GaN connecting segment is pretty thin,the piezoelectric charges generated by stress are proposed to have only a limited effect on the photocurrent density.Therefore,both the stable on-off switching characteristics and photocurrent densities can still be achieved after being bent 400 times.With an excellent flexibility,this work creates opportunities for technological applications of bidirectional photocurrent PDs in flexible optoelectronic devices,e.g.,wearable intelligent sensors.

关键词： Flexible photodetector Bidirectional photocurrent Lift-off GaN-based nanowires Hydrogel Self-powered device

Fluorogenic sensing of amorphous aggregates,amyloid fibers,and chaperone activity via a near-infrared aggregation-induced emission-active probe

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Aggregate 2024年第1期5卷 309-320页

作者： Wei He yuanyuan Yang Yuhui Qian Zhuoyi Chen Yongxin Zheng Wenping zhao Chenxu Yan Zhiqian Guo Shu Quan State Key Laboratory of Bioreactor Engineering Shanghai Collaborative Innovation Center for Biomanufacturing(SCICB)East China University of Science and TechnologyShanghaiChina Key Laboratory for Advanced Materials and Joint International Research Laboratory of Precision Chemistry and Molecular Engineering Shanghai Key Laboratory of Functional Materials ChemistryFrontiers Science Center for Materiobiology and Dynamic ChemistryInstitute of Fine ChemicalsSchool of Chemistry and Molecular EngineeringEast China University of Science and TechnologyShanghaiChina Shanghai Frontiers Science Center of Optogenetic Techniques for Cell Metabolism East China University of Science and TechnologyShanghaiChina

The presence of protein aggregates in numerous human diseases underscores the significance of detecting these aggregates to comprehend disease mechanisms and develop novel therapeutic approaches for combating these disorders.Despite the development of various biosensors and fluorescent probes that selectively target amyloid fibers or amorphous aggregates,there is still a lack of tools capable of simultaneously detecting both types of aggregates.Herein,we demonstrate the quantitative discernment of amorphous aggregates by QM-FN-SO3,an aggregationinduced emission(AIE)probe initially designed for detecting amyloid fibers.This probe easily penetrates the membranes of the widely-used prokaryotic model organism Escherichia coli,enabling the visualization of both amorphous aggregates and amyloid fibers through near-infrared fluorescence.Notably,the probe exhibits sensitivity in distinguishing the varying aggregation propensities of proteins,regardless of whether they form amorphous aggregates or amyloid fibers in vivo.These properties contribute to the successful application of the QM-FN-SO3 probe in the subsequent investigation of the antiaggregation activities of two outer membrane protein(OMP)chaperones,both in vitro and in their physiological environment.Overall,our work introduces a near-infrared fluorescent chemical probe that can quantitatively detect amyloid fibers and amorphous aggregates with high sensitivity in vitro and in vivo.Furthermore,it demonstrates the applicability of the probe in chaperone biology and its potential as a high-throughput screening tool for protein aggregation inhibitors and folding factors.

关键词： aggregation-induced emission fluorescence molecular chaperone protein aggregation

Electron-transporting boron-doped polycyclic aromatic hydrocarbons:Facile synthesis and heteroatom doping positions-modulated optoelectronic properties

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Chinese Chemical Letters 2024年第4期35卷 447-451页

作者： Tingting Huang Zhuanlong Ding Hao Liu Ping-An Chen Longfeng zhao yuanyuan Hu Yifan Yao Kun Yang Zebing Zeng Key Laboratory of Chemo/Biosensing and Chemometrics College of Chemistry and Chemical EngineeringHunan UniversityChangsha 410082China Shenzhen Research Institute of Hunan University Shenzhen 518000China Key Laboratory for Micro/Nano Optoelectronic Devices of Ministry of Education and Hunan Provincial Key Laboratory of Low-Dimensional Structural Physics and Devices School of Physics and Electronics Hunan UniversityChangsha 410082China

While heteroatom doping serves as a powerful strategy for devising novel polycyclic aromatic hydrocarbons(PAHs), the further fine-tuning of optoelectronic properties via the precisely altering of doping patterns remains a challenge. Herein, by changing the doping positions of heteroatoms in a diindenopyrene skeleton, we report two isomeric boron, sulfur-embedded PAHs, named Anti-B_(2)S_(2) and Syn-B_(2)S_(2), as electron transporting semiconductors. Detailed structure-property relationship studies revealed that the varied heteroatom positions not only change their physicochemical properties, but also largely affect their solid-state packing modes and Lewis base-triggered photophysical responses. With their low-lying frontier molecular orbital levels, n-type characteristics with electron mobilities up to 1.5 × 10^(-3)cm^(2)V^(-1)s^(-1)were achieved in solution-processed organic field-effect transistors. Our work revealed the critical role of controlling heteroatom doping patterns for designing advanced PAHs.

关键词： Polycyclic aromatic hydrocarbon Optoelectronic properties Heteroatom doping n-Type organic semiconductors Structure–property relationship