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Targeting lncRNA16 by GalNAc-siRNA conjugates facilitates chemotherapeutic sensibilization via the HBB/NDUFAF5/ROS pathway

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Science China(Life Sciences) 2024年第4期67卷 663-679页

作者： Yanfang Liu Yan Wang Bing Liu Wenzhong Liu Yuanyuan Ma Yiren Cao Shi Yan Panpan Zhang Lixin Zhou Qimin Zhan Nan Wu key laboratory of Carcinogenesis and translational Research(Ministry of Education/beijing) Department of Thoracic Surgery IIPeking University Cancer Hospital and InstituteBeijing 100142China key laboratory of Carcinogenesis and translational Research(Ministry of Education/beijing) Laboratory of Molecular OncologyPeking University Cancer Hospital and InstituteBeijing 100142China key laboratory of Carcinogenesis and translational Research(Ministry of Education/beijing) Department of Thoracic Oncology IIPeking University Cancer Hospital and InstituteBeijing 100142China key laboratory of Carcinogenesis and translational Research(Ministry of Education) Department of PathologyPeking University Cancer Hospital and InstituteBeijing 100142China Peking University International Cancer Institute Beijing 100191China Institute of Cancer Research Shenzhen Bay LaboratoryShenzhen 518132China

Chemoresistance is a significant barrier to effective cancer *** mechanisms for chemoresistance include reactive oxygen species(ROS)accumulation and expression of chemoresistance-promoting ***,we report a novel function of lncRNA16 in the inhibition of ROS generation and the progression of *** analyzing the serum levels of lncRNA16 in a cohort of 35 patients with non-small cell lung cancer(NSCLC)and paired serum samples pre-and post-treatment from 10 NSCLC patients receiving neoadjuvant platinum-based chemotherapy,performing immunohistochemistry(IHC)assays on 188 NSCLC tumor samples,using comprehensive identification of RNA-binding proteins by mass spectrometry(ChIRP-MS)assays,as well as RNA immunoprecipitation(RIP)and RNA pull-down analyses,we discovered that patients with increased serum levels of lncRNA16 exhibited a poor response to platinum-based *** expression of hemoglobin subunit beta(HBB)and NDUFAF5 significantly increases with the development of ***16 binds to HBB and promotes HBB accumulation by inhibiting ***16 can also inhibit ROS generation via the HBB/NDUFAF5 axis and function as a scaffold to facilitate the colocalization of HBB and NDUFAF5 in the ***,preclinical studies in mouse models of chemo-resistant NSCLC have suggested that lncRNA16 targeting by trivalent N-acetylgalactosamine(GalNAc)-conjugated siRNA restores chemosensitivity and results in tumor growth inhibition with no detectable toxicity in ***,lncRNA16 is a promising therapeutic target for overcoming chemoresistance,and the combination of first-line platinum-based chemotherapy with lncRNA16 intervention can substantially enhance anti-tumor efficacy.

关键词： chemoresistance lncRNARNA interference ROs chemosensitizer

Value of multiple models of diffusion-weighted imaging to predict hepatic lymph node metastases in colorectal liver metastases patients

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World Journal of Gastroenterology 2024年第4期30卷 308-317页

作者： Hai-Bin Zhu Bo Zhao Xiao-Ting Li Xiao-Yan Zhang Qian Yao Ying-Shi Sun key laboratory of Carcinogenesis and translational Research(Ministry of Education/beijing) Department of RadiologyPeking University Cancer Hospital and InstituteBeijing 100142China key laboratory of Carcinogenesis and translational Research(Ministry of Education/beijing) Department of PathologyPeking University Cancer Hospital and InstituteBeijing 100142China

BACKGROUND About 10%-31% of colorectal liver metastases(CRLM)patients would concomitantly show hepatic lymph node metastases(LNM),which was considered as sign of poor biological behavior and a relative contraindication for liver *** to now,there’s still lack of reliable preoperative methods to assess the status of hepatic lymph nodes in patients with CRLM,except for pathology examination of lymph node after *** To compare the ability of mono-exponential,bi-exponential,and stretchedexponential diffusion-weighted imaging(DWI)models in distinguishing between benign and malignant hepatic lymph nodes in patients with CRLM who received neoadjuvant chemotherapy prior to *** In this retrospective study,97 CRLM patients with pathologically confirmed hepatic lymph node status underwent magnetic resonance imaging,including DWI with ten b values before and after *** parameters,such as the apparent diffusion coefficient from the mono-exponential model,and the true diffusion coefficient,the pseudo-diffusion coefficient,and the perfusion fraction derived from the intravoxel incoherent motion model,along with distributed diffusion coefficient(DDC)andαfrom the stretched-exponential model(SEM),were *** parameters before and after chemotherapy were compared between positive and negative hepatic lymph node groups.A nomogram was constructed to predict the hepatic lymph node *** reliability and agreement of the measurements were assessed using the coefficient of variation and intraclass correlation *** Multivariate analysis revealed that the pre-treatment DDC value and the short diameter of the largest lymph node after treatment were independent predictors of metastatic hepatic lymph nodes.A nomogram combining these two factors demonstrated excellent performance in distinguishing between benign and malignant lymph nodes in CRLM patients,with an area under the curve of ***,parameters from SEM sho

关键词： Colorectal cancer Individualized treatment Diffusion magnetic resonance imaging Intravoxel incoherent motion Liver

Helicobacter pylori and immunotherapy for gastrointestinal cancer

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The Innovation 2024年第2期5卷 51-60页

作者： Keren Jia Yang Chen Yi Xie Xicheng Wang Yajie Hu Yu Sun Yanshuo Cao Liyan Zhang Yakun Wang Zhenghang Wang Zhihao Lu Jian Li Xiaotian Zhang Lin Shen key laboratory of Carcinogenesis and translational Research(Ministry of Education/beijing) Department of Gastrointestinal OncologyPeking University Cancer Hospital&InstituteBeijing 100142China key laboratory of Carcinogenesis and translational Research(Ministry of Education/beijing) Department of PathologyPeking University Cancer Hospital&InstituteBeijing 100142China

Helicobacter pylori infection is associated with the risk of gastrointestinal(GI)cancers;however,its impact on immunotherapy for GI cancers remains *** this study,we included 10,122 patients who underwent ^(13)C-urea breath *** 636 patients with Epstein-Barr virus–negative microsatellite-stable gastric cancer(GC)who were treated with anti-PD-1/PD-L1 therapy,***–positive patients exhibited significantly longer immune-related progression-free survival(irPFS)compared with ***–negative patients(6.97 months versus 5.03 months,p<0.001,hazard ratio[HR]0.76,95%confidence interval[CI]0.62–0.95,p=0.015).Moreover,the ***–positive group demonstrated a trend of 4 months longer median immune-related overall survival(irOS)than the ***–negative ***–positive GC displayed higher densities of PD-L1+cells and nonexhausted CD8+T cells,indicative of a“hot”tumor *** analysis revealed that ***–positive GC shared molecular characteristics similar to those of immunotherapy-sensitive ***,***–positive patients with DNA mismatch repair–deficient(dMMR)/microsatellite instability–high(MSI-H)colorectal adenocarcinoma and esophageal squamous cell carcinoma(ESCC)had shorter irPFS compared with ***–negative patients(16.13 months versus not reached,p=0.042,HR 2.26,95%CI 1.13–4.50,p=0.021 and 5.57 months versus 6.97 months,p=0.029,HR 1.59,95%CI 1.14–2.23,p=0.006,respectively).The difference in irOS between ***–positive and–negative patients had the same trend as that between dMMR/MSI-H colorectal adenocarcinoma and ESCC *** also identified a trend of shorter irPFS and irOS in ***–positive liver cancer and pancreatic cancer *** summary,our findings supported that *** infection is a beneficial factor for GC immunotherapy by shaping hot tumor ***,in dMMR/MSI-H colorectal adenocarcinoma and ESCC patients,*** adversely affects the efficacy of immunothera

关键词： immunotherapy gastrointestinal pylori

Clinical efficacy and identification of factors confer resistance to afatinib(tyrosine kinase inhibitor)in EGFR-overexpressing esophageal squamous cell carcinoma

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Signal Transduction and Targeted Therapy 2024年第7期9卷 3130-3140页

作者： Yanni Wang Chang Liu Huan Chen Xi Jiao Yujiao Wang Yanshuo Cao Jian Li Xiaotian Zhang Yu Sun Na Zhuo Fengxiao Dong Mengting Gao Fengyuan Wang Liyuan Dong Jifang Gong Tianqi Sun Wei Zhu Henghui Zhang Lin Shen Zhihao Lu key laboratory of Carcinogenesis and translational Research(Ministry of Education/beijing) Department of Gastrointestinal OncologyPeking University Cancer Hospital and InstituteBeijingChina Genecast Biotechnology Co. LtdWuxiPR China State key laboratory of Holistic Integrative Management of Gastrointestinal Cancers Beijing Key Laboratory of Carcinogenesis and Translational ResearchDepartment of Gastrointestinal OncologyPeking University Cancer Hospital and InstituteBeijingChina key laboratory of Carcinogenesis and translational Research(Ministry of Education) Department of PathologyPeking University Cancer Hospital and InstituteBeijingChina Precision Scientific(beijing)Co. Ltd.BeijingChina Generulor Company Bio-X Lab ZhuhaiGuangdongChina Biomedical Innovation Center Beijing Shijitan HospitalCapital Medical UniversityBeijingChina beijing key laboratory for Therapeutic Cancer Vaccines Beijing Shijitan HospitalCapital Medical UniversityBeijingChina

Epidermal growth factor receptor(EGFR)is reportedly overexpressed in most esophageal squamous cell carcinoma(ESCC)patients,but anti-EGFR treatments offer limited survival *** preclinical data showed the promising antitumor activity of afatinib in EGFR-overexpressing *** proof-of-concept,phase II trial assessed the efficacy and safety of afatinib in pretreated metastatic ESCC patients(n=41)with EGFR overexpression(NCT03940976).The study met its primary endpoint,with a confirmed objective response rate(ORR)of 39%in 38 efficacy-evaluable patients and a median overall survival of 7.8 months,with a manageable toxicity *** analysis of pretreatment tumors revealed that neurotrophic receptor tyrosine kinase 2(NTRK2)was negatively associated with afatinib sensitivity and might serve as a predictive biomarker,irrespective of EGFR ***,knocking down or inhibiting NTRK2 sensitized ESCC cells to afatinib *** study provides novel findings on the molecular factors underlying afatinib resistance and indicates that afatinib has the potential to become an important treatment for metastatic ESCC patients.

关键词： esophageal squamous expressing

Advances in MET tyrosine kinase inhibitors in gastric cancer

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Cancer Biology & medicine 2024年第6期21卷 484-498页

作者： Yifan Zhang Lin Shen Zhi Peng key laboratory of Carcinogenesis and translational Research(Ministry of Education) Department of Gastrointestinal OncologyPeking University Cancer Hospital&InstituteBeijing 100142China State key laboratory of Holistic Integrative Management of Gastrointestinal Cancers Beijing Key Laboratory of Carcinogenesis and Translational ResearchDepartment of Gastrointestinal OncologyPeking University Cancer Hospital&InstituteBeijing 100142China

Gastric cancer is among the most frequently occurring cancers and a leading cause of cancer-related deaths *** gastric cancer is highly heterogenous and comprised of different subtypes with distinct molecular and clinical characteristics,the management of gastric cancer calls for better-defined,biomarker-guided,molecular-based treatment *** is a receptor tyrosine kinase mediating important physiologic processes,such as embryogenesis,tissue regeneration,and wound ***,mounting evidence suggests that aberrant MET pathway activation contributes to tumour proliferation and metastasis in multiple cancer types,including gastric cancer,and is associated with poor patient *** such,MET-targeting therapies are being actively developed and promising progress has been demonstrated,especially with MET tyrosine kinase *** review aims to briefly introduce the role of MET alterations in gastric cancer and summarize in detail the current progress of MET tyrosine kinase inhibitors in this disease area with a focus on savolitinib,tepotinib,capmatinib,and *** on current knowledge,this review further discusses existing challenges in MET alterations testing,possible resistance mechanisms to MET inhibitors,and future directions of MET-targeting therapies.

关键词： Gastric cancer MET alterations MET tyrosine kinase inhibitors savolitinib MET testing

Enhanced Precision Therapy of Multiple Myeloma Through Engineered Biomimetic Nanoparticles with Dual Targeting

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Engineering 2024年第5期36卷 178-192页

作者： Ruogu Qi Shanshan Wang Jiayi Yu Tianming Lu Zhiqiang Bi Weibo Liu Yuanyuan Guo Yong Bian Jianliang Shen Xuesong Zhang Wenhao Hu School of medicine Nanjing University of Chinese MedicineNanjing 210023China laboratory Animal Center Nanjing University of Chinese MedicineNanjing 210023China key laboratory of Carcinogenesis and translational Research Ministry of Education/BeijingDepartment of Radiation OncologyBeijing Cancer HospitalBeijing 100142China Department of Orthopedics The Fourth Medical CenterThe Chinese People’s Liberation Army General HospitalBeijing 100853China State key laboratory of Ophthalmology Optometry and Vision ScienceSchool of Biomedical EngineeringWenzhou Medical UniversityWenzhou 325027China

Multiple myeloma(MM)is the second most prevalent hematological *** MM treatment strategies are hampered by systemic toxicity and suboptimal therapeutic *** study addressed these limitations through the development of a potent MM-targeting chemotherapy strategy,which capitalized on the high binding affinity of alendronate for hydroxyapatite in the bone matrix and the homologous targeting of myeloma cell membranes,termed T-PB@*** results from our investigations highlight the considerable bone affinity of T-PB@M,both in vitro and in ***,this material demonstrated a capability for drug release triggered by low pH ***,T-PB@M induced the generation of reactive oxygen species and triggered cell apoptosis through the poly(ADP-ribose)polymerase 1(PARP1)-Caspase-3-B-cell lymphoma-2(Bcl-2)pathway in MM ***,T-PB@M preferentially targeted bone-involved sites,thereby circumventing systemic toxic side effects and leading to prolonged survival of MM orthotopic ***,this designed target-MM nanocarrier presents a promising and potentially effective platform for the precise treatment of MM.

关键词： Multiple myeloma Bortezomib Drug delivery Dual targeting Controlled release

Dopaminergic Remodeling During a Critical Developmental Window:Linking Drug Use to Adult Aggression

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Neuroscience Bulletin 2024年第6期40卷 845-848页

作者： Dadao An Lingyan Zheng Zhengyi Xu Yanrong Zheng Zhong Chen key laboratory of Neuropharmacology and translational medicine of Zhejiang Province Zhejiang Chinese Medical UniversityHangzhou310053China

Behaviors can be shaped and modulated by the dopamine system,which can be remodeled in adolescents due to environmental factors,including pharmacologic exposure,stress,and rewarding experiences,leading to various adolescentonset neuropsychiatric disorders[1-3].A deficiency of dopamine transporter(DAT),responsible for reuptaking extracellular DA.

关键词： Window shaped Dopamine

Genomic characterization of peritoneal lavage cytology-positive gastric cancer

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Chinese Journal of Cancer Research 2024年第1期36卷 66-77页

作者： Zhouqiao Wu Tingfei Gu Changxian Xiong Jinyao Shi Jingpu Wang Ting Guo Xiaofang Xing Fei Pang Ning He Rulin Miao Fei Shan Yuan Zhou Ziyu Li Jiafu Ji key laboratory of Carcinogenesis and translational Research(Ministry of Education/beijing) Gastrointestinal Cancer CenterPeking University Cancer Hospital&InstituteBeijing 100142China Department of Biomedical Informatics Department of Physiology and PathophysiologyCenter for Noncoding RNA MedicineMOE Key Lab of Cardiovascular SciencesSchool of Basic Medical SciencesPeking UniversityBeijing 100191China State key laboratory of Holistic Integrative Management of Gastrointestinal Cancers Beijing Key Laboratory of Carcinogenesis and Translational ResearchGastrointestinal Cancer CenterPeking University Cancer Hospital&InstituteBeijing 100142China

Objective: Positive peritoneal lavege cytology(CY1) gastric cancer is featured by dismal prognosis, with high risks of peritoneal metastasis. However, there is a lack of evidence on pathogenic mechanism and signature of CY1and there is a continuous debate on CY1 therapy. Therefore, exploring the mechanism of CY1 is crucial for treatment strategies and targets for CY1 gastric ***: In order to figure out specific driver genes and marker genes of CY1 gastric cancer, and ultimately offer clues for potential marker and risk assessment of CY1, 17 cytology-positive gastric cancer patients and 31matched cytology-negative gastric cancer patients were enrolled in this study. The enrollment criteria were based on the results of diagnostic laparoscopy staging and cytology inspection of exfoliated cells. Whole exome sequencing was then performed on tumor samples to evaluate genomic characterization of cytology-positive gastric ***: Least absolute shrinkage and selection operator(LASSO) algorithm identified 43 cytology-positive marker genes, while Mut Sig CV identified 42 cytology-positive specific driver genes. CD3G and CDKL2 were both driver and marker genes of CY1. Regarding mutational signatures, driver gene mutation and tumor subclone architecture, no significant differences were observed between CY1 and negative peritoneal lavege cytology(CY0).Conclusions: There might not be distinct differences between CY1 and CY0, and CY1 might represent the progression of CY0 gastric cancer rather than constituting an independent subtype. This genomic analysis will thus provide key molecular insights into CY1, which may have a direct effect on treatment recommendations for CY1and CY0 patients, and provides opportunities for genome-guided clinical trials and drug development.

关键词： Cytology gastric carcinoma peritoneal metastasis whole exome sequencing

Boosting synergism of chemo- and immunotherapies via switching paclitaxel-induced apoptosis to mevalonate metabolism-triggered ferroptosis by bisphosphonate coordination lipid nanogranules

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Acta Pharmaceutica Sinica B 2024年第2期14卷 836-853页

作者： Ge Song Minghui Li Shumin Fan Mengmeng Qin Bin Shao Wenbing Dai Hua Zhang Xueqing Wang Bing He Qiang Zhang beijing key laboratory of Molecular Pharmaceutics and New Drug Delivery Systems School of Pharmaceutical SciencesPeking UniversityBeijing 100191China State key laboratory of Natural and Biomimetic Drugs School of Pharmaceutical SciencesPeking UniversityBeijing 100191China Department of Medical Oncology Key Laboratory of Carcinogenesis and Translational Research(Ministry of Education)Peking University Cancer HospitalBeijing 100142China

Conventional chemotherapy based on cytotoxic drugs is facing tough challenges recently following the advances of monoclonal antibodies and molecularly targeted *** is critical to inspire new potential to remodel the value of this classical therapeutic ***,we fabricate bisphosphonate coordination lipid nanogranules(BC-LNPs)and load paclitaxel(PTX)to boost the chemo-and immuno-therapeutic synergism of cytotoxic *** in BC-LNPs@PTX,a bisphosphonate to block mevalonate metabolism,works as both the structure and drug constituent in nanogranules,where alendronate coordinated with calcium ions to form the particle *** synergy of alendronate enhances the efficacy of paclitaxel,suppresses tumor metastasis,and alters the cytotoxic *** from the paclitaxel-induced apoptosis,the involvement of alendronate inhibits the mevalonate metabolism,changes the mitochondrial morphology,disturbs the redox homeostasis,and causes theaccumulation of mitochondrial ROS and lethal lipid peroxides(LPO).These factors finally trigger the ferroptosis of tumor cells,an immunogenic cell death mode,which remodels the suppressive tumor immune microenvironment and synergizes with ***,by switching paclitaxel-induced apoptosis to mevalonate metabolism-triggered ferroptosis,BC-LNPs@PTX provides new insight into the development of cytotoxic drugs and highlights the potential of metabolism regulation in cancer therapy.

关键词： Bisphosphonate coordinationlipid nanogranules Ferroptosis Mevalonatemetabolism Mitochondrial metabolism Nano-systematic biology