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Initial Approach to the Cellular Irradiation Injury of Human Pancreatic Carcinoma Cell Line MIA PaCa-2 by High Dose per Fraction

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Clinical oncology and cancer researeh 2010年第6期7卷 352-358页

作者： Zhi-zhen WANG Hai-li YU Zhi-yong YUAN Ping WANG Department of Radiation therapy Tianjin Medical University Cancer Institute and Hospital Tianjin Key Laboratory of cancer Prevention and therapy Tianjin 300060 China.

OBJECTIVE To investigate an initial approach of radiotherapy, which produces cellular radiation injury by high dose in one fraction. METHODS Human pancreatic carcinoma cell line MIA PaCa-2, was cultivated and divided into 5 groups： 0, 2, 5, 10, 17 Gy. Cultivated cells were irradiated by 6MV-X ray in one fraction. Analysis were done as follows： comet assay, which assessed the level of DNA damage in the treated cells right after the cell was irradiated, flow cytometry, which was performed at 0, 6, 12, 24, 36 h after the cell line treated to ladder, which quantitatively asses changes of its cell cycle, DNA assessed the degree of DNA injury after 6 and 12 h, and histological examination, which analyzed cellular morphology after 24 h. RESULTS （1） After X-ray irradiated, the morphological change of human pancreatic carcinoma cell line （MIA PaCa-2） was mainly swelling. （2） When the dose of radiation was lower than 10 Gy, increasing the dose could greatly improve cell necrosis, apoptosis and blockage of cell cycle in GJM phase, which was consistent with the theory of radiation biology. （3） When radiation dose was more than the 10 Gy, the peak of apoptotic necrosis appeared strong and early. （4） The degree of DNA injury was also related to the dose of radiation therapy and most obvious in the 10 Gy group and not so obvious in the 17 Gy group. （5） When dose was less than 10 Gy, DNA ladder was a single electrophoretic band; in the 10 Gy group, the electrophoresis showed a multiple ladder band; when dose was more than 10 Gy, a vague and irregular band appeared on the electrophoresis. CONCLUSION Oncotic necrosis may be the main cell death style when dose per fraction is high, which differs from conventional dose fraction radiation therapy.

关键词： dose-response relationship drug necrosis irradiation injury.

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Hypoxic microenvironment induced spatial transcriptome changes in pancreatic cancer

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cancer Biology & Medicine 2021年第2期18卷 616-630页

作者： Huizhi Sun Danfang Zhang Chongbiao Huang Yuhong Guo Zhao Yang Nan Yao Xueyi Dong Runfen Cheng Nan Zhao Jie Meng Baocun Sun Jihui Hao Tianjin Medical University cancer Institute and Hospital National Clinical Research Center for CancerKey Laboratory of Cancer Prevention and TherapyTianjinTianjin’s Clinical Research Center for CancerTianjin 300060China Department of Pathology School of Basic Medical ScienceTianjin Medical UniversityTianjin 300070China

Objective: Hypoxia is a significant feature of solid tumors, including pancreatic ductal adenocarcinoma(PDAC). It is associated with tumor invasion, metastasis, and drug resistance. However, the spatial distribution of hypoxia-related heterogeneity in PDAC remains ***: Spatial transcriptomics(STs), a new technique, was used to investigate the ST features of engrafted human PDAC in the ischemic hind limbs of nude mice. Transcriptomes from ST spots in the hypoxic tumor and the control were clustered using differentially-expressed genes. These data were compared to determine the spatial organization of hypoxia-induced heterogeneity in PDAC. Clinical relevance was validated using the Tumor cancer Genome Atlas and KM-plotter databases. The CMAP website was used to identify molecules that may serve as therapeutic targets for ***: ST showed that the tumor cell subgroups decreased to 7 subgroups in the hypoxia group, compared to 9 subgroups in the control group. Different subgroups showed positional characteristics and different gene signatures. Subgroup 6 located at the invasive front showed a higher proliferative ability under hypoxia. Subgroup 6 had active functions including cell proliferation, invasion, and response to stress. Expressions of hypoxia-related genes, LDHA, TPI1, and ENO1, induced changes. CMAP analysis indicated that ADZ-6482, a PI3 K inhibitor, was targeted by the invasive subgroup in hypoxic ***: This study is the first to describe hypoxic microenvironment-induced spatial transcriptome changes in PDAC, and to identify potential treatment targets for PDAC. These data will provide the basis for further investigations of the prognoses and treatments of hypoxic tumors.

关键词： Pancreatic cancer hypoxia spatial transcriptomic

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DNA-PK inhibition by M3814 enhances chemosensitivity in non-small cell lung cancer

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Acta Pharmaceutica Sinica B 2021年第12期11卷 3935-3949页

作者： Manni Wang Siyuan Chen Yuquan Wei Xiawei Wei Laboratory of Aging Research and cancer drug Target State Key Laboratory of Biotherapy and Cancer CenterNational Clinical Research Center for GeriatricsWest China HospitalSichuan UniversityChengdu 610000China

A significant proportion of non-small cell lung cancer(NSCLC) patients experience accumulating chemotherapy-related adverse events,motivating the design of chemosensitizating *** main cytotoxic damage induced by chemotherapeutic agents is DNA double-strand breaks(DSB).It is thus conceivable that DNA-dependent protein kinase(DNA-PK) inhibitors which attenuate DNA repair would enhance the anti-tumor effect of *** present study aims to systematically evaluate the efficacy and safety of a novel DNA-PK inhibitor M3814 in synergy with chemotherapies on *** identified increased expression of DNA-PK in human NSCLC tissues which was associated with poor prognosis.M3814 potentiated the anti-tumor effect of paclitaxel and etoposide in A549,H460 and H1703 NSCLC cell *** the four combinations based on two NSCLC xenograft models and two chemotherapy,we also observed tumor regression at tolerated doses in ***,we identified a P53-dependent accelerated senescence response by M3814 following treatment with paclitaxel/*** present study provides a theoretical basis for the use of M3814 in combination with paclitaxel and etoposide in clinical practice,with hope to aid the optimization of NSCLC treatment.

关键词： M3814 Paclitaxel Etoposide DNA-dependent protein kinase Non-small cell lung cancer DNA repair Cell senescence Chemosensitization

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Effects of diammonium glycyrrhizinate on hepatic and intestinal UDP-Glucuronosyltransferases in rats: Implication in herb-drug interactions

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Chinese Journal of Natural Medicines 2016年第7期14卷 534-540页

作者： LI Fei-Yan XIE Hao WENG Lin WANG Hong CAO Li-Juan HAO Hai-Ping WANG Guang-Ji State Key Laboratory of Natural Medicines Key Laboratory of Drug Metabolism and Pharmacokinetics China Pharmaceutical University Department of Good Clinical Practice Zhejiang Cancer Hospital

Glycyrrhizin is a major bioactive component of liquorice, which exerts multiple biochemical and pharmacological activities and is frequently used in combination with other drugs in the clinic. Mycophenolate mofetil(MMF), an immunosuppressant widely used in transplant patients, is metabolized by UDP-glucuronyltransferases(UGTs). Although significant evidence supports that glycyrrhizin could interact with the cytochrome P450s(CYPs), few studies have addressed its effects on UGTs. The present study aimed at investigating the regulatory effects of diammonium glycyrrhizinate(GLN) on UGTs in vitro and in vivo. We found that long-term administration of GLN in rats induced overall metabolism of MMF, which might be due to the induction of UGT1A protein expression. Hepatic UGT1A activity and UGT1A mRNA and protein expression were significantly increased in GLN-treated rats. UGT1A expression levels were also increased in the intestine, contradicting with the observed decrease in intestinal UGT1A activities. This phenomenon may be attributed to different concentrations of glycyrrhetinic acid(GA) in liver and intestine and the inhibitory effects of GA on UGT1A activity. In conclusion, our study revealed that GLN had multiple effects on the expression and activities of UGT1A isoforms, providing a basis for a better understanding of interactions between GLN and other drugs.

关键词： Diammonium glycyrrhizinate UDP-glucuronosyltransferase Sprague-Dawley rat drug-drug interaction

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Nanovaccines for cancer immunotherapy:Current knowledge and future perspectives

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Chinese Chemical Letters 2023年第8期34卷 57-68页

作者： Yiming Wu Zhe Zhang Yuquan Wei Zhiyong Qian Xiawei Wei Laboratory of Aging Research and cancer drug Target State Key Laboratory of Biotherapy and Cancer CenterNational Clinical Research Center for GeriatricsWest China HospitalSichuan UniversityChengdu 610041China

cancer immunotherapy harnesses the immune system to attack tumors and has received extensive attention in recent *** vaccines as an important branch of immunotherapy are designed for delivering tumor antigens to antigen-presenting cells(APCs)to stimulate a strong immune response to against tumors,representing a potentially therapeutic and prophylactic effect with the long-term anticancer ***,the disappointing outcomes of their clinical use might be attributed to dilemma in antigen selection,immunogenicity,lymph nodes(LNs)targeting ability,lysosomal escape ability,immune evasion,***,aiming to overcome these barriers,has been utilized in cancer vaccine development for *** preclinical and clinical studies demonstrate positive results in nanomaterials-based cancer vaccines with considerable improvement in the vaccine *** this review,we systematically introduced the characteristics of nanovaccines and highlighted the different types of nanomaterials used for cancer vaccine *** addition,the opportunities and challenges of the emerging nanotechnology-based cancer vaccines were discussed.

关键词： cancer immunotherapy cancer vaccines Nanoparticles Antitumor immune response Clinical transformation

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Intranasal boosting with RBD-HR protein vaccine elicits robust mucosal and systemic immune responses

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Genes & Diseases 2024年第4期11卷 327-339页

作者： Li Chen Wenyan Ren Hong Lei Jiayu Wang Haiying Que Dandan Wan Aqu Alu Dandan Peng Minyang Fu Weiqi Hong Yuhe Huang Xiangrong Song Guangwen Lu Xiawei Wei Laboratory of Aging Research and cancer drug Target State Key Laboratory of Biotherapy and Cancer CenterNational Clinical Research Center for GeriatricsWest China HospitalSichuan UniversityChengduSichuan 610041China

The emergence of severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)variants has decreased the efficacy of SARs-CoV-2 vaccines in containing coronavirus disease 2019(CoVID-19)over time,and booster vaccination strategies are urgently necessitated to achieve sufficient *** immunization can improvemucosal immunity,offer-ing protection against the infection and sustaining the spread of *** this study,an intranasal booster of the RBD-HR vaccine after two doses of the mRNA vaccine significantly increased the levels of specific binding antibodies in serum,nasal lavage fluid,and bronchoal-veolar lavage fluid compared with only two doses of mRNA *** intranasal boosting with the RBD-HR vaccine,the levels of serum neutralizing antibodies against prototype and variant strains of SARS-Cov-2 pseudoviruses weremarkedly higher than those in mice receiving mRNA vaccine alone,and intranasal boosting with the RBD-HR vaccine also inhibited the bind-ing of RBD to hACE2 ***,the heterologous intranasal immunization regimen promoted extensive memory T cell responses and activated CD103+dendritic cells in the respiratory mucosa,and potently enhanced the formation of T follicular helper cells and germinal center B cells in vital immune organs,including mediastinal lymph nodes,inguinal lymph nodes,and ***,these data infer that heterologous intranasal boosting with the RBD-HR vaccine elicited broad protective immunity against SARS-CoV-2 both locallyandsystemically.

关键词： Heterologous immunization Intranasal immunization mRNA vaccine SARS-CoV-2 Subunitprotein vaccine

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Molecular glue triggers degradation of PHGDH by enhancing the interaction between DDB1 and PHGDH

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Acta Pharmaceutica Sinica B 2024年第9期14卷 4001-4013页

作者： Ziqi Huang Kun Zhang Yurui Jiang Mengmeng Wang Mei Li Yuda Guo Ruolin Gao Ning Li Chenyang Wang Jia Chen Jiefu Wang Ning Liu Xiang Liu Shuangwei Liu Mingming Wei Cheng Yang Guang Yang The State Key Laboratory of Medicinal Chemical Biology College of Life SciencesCollege of PharmacyNankai UniversityTianjin 300071China Tianjin Medical University cancer Institute and Hospital National Clinical Research Center for CancerTianjin’s Clinical Research Center for CancerKey Laboratory of Cancer Prevention and TherapyTianjin 300060China

cancer stem cells(CSCs)play a pivotal role in tumor initiation,proliferation,metastasis,drug resistance,and ***,targeting CSCs has emerged as a promising avenue for cancer ***,3-phosphoglycerate dehydrogenase(PHGDH)has been identified as being intricately associated with the regulation of numerous cancer stem ***,reports detailing the functional regulators of PHGDH that can mitigate the stemness across cancer types are *** this study,the novel“molecular glue”LXH-3-71 was identified,and it robustly induced degradation of PHGDH,thereby modulating the stemness of colorectal cancer cells(CRCs)both in vitro and in ***,LXH-3-71 was observed to form a dynamic chimera,between PHGDH and the DDB1-CRL E3 *** insights not only elucidate the anti-CSCs mechanism of the lead compound but also suggest that degradation of PHGDH may be a more viable therapeutic strategy than the development of PHGDH ***,compound LXH-3-71 was leveraged as a novel ligand for the DDB1-CRL E3 ligase,facilitating the development of new PROTAC molecules targeting EGFR and CDK4 degradation.

关键词： Molecular glue Targeted protein degradation PHGDH cancer stem cells PROTACs

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Targeting H3K36 methyltransferases NSDs:a promising strategy for tumor targeted therapy

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Signal Transduction and Targeted therapy 2021年第7期6卷 1933-1934页

作者： Xuerun Peng Qian Peng Lei Zhong Personalized drug therapy Key Laboratory of Sichuan Province Department of PharmacySichuan Provincial People's HospitalSchool of MedicineUniversity of Electronic Science and Technology of ChinaChengduSichuanChina Radiation Oncology Key Laboratory of Sichuan Province Sichuan Cancer Hospital&InstituteSichuan Cancer CenterSchool of MedicineUniversity of Electronic Science and Technology of ChinaChengduChina

Recently,two studies published in Nature identified genetic changes in the nuclear receptor-binding SET domain protein(NSD)family of histone methyltransferases as oncogenic drivers in some malignancies,and revealed th... 详细信息

关键词： methyltransferase targeted therapy

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Targeting RAS-RAF-MEK-ERK signaling pathway in human cancer:Current status in clinical trials

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Genes & Diseases 2023年第1期10卷 76-88页

作者： Yanlin Song Zhenfei Bi Yu Liu Furong Qin Yuquan Wei Xiawei Wei Laboratory of Aging Research and cancer drug Target State Key Laboratory of Biotherapy and Cancer CenterNational Clinical Research Center for GeriatricsWest China HospitalSichuan UniversityChengduSichuan610041China

Molecular target inhibitors have been regularly approved by Food and drug Administration(FDA)for tumor treatment,and most of them intervene in tumor cell proliferation and *** RAS-RAF-MEK-ERK pathway is a conserved signaling pathway that plays vital roles in cell proliferation,survival,and *** aberrant activation of the RAS-RAF-MEK-ERK signaling pathway induces *** 33%of tumors harbor RAS mutations,while 8%of tumors are driven by RAF *** efforts have been dedicated to targeting the signaling pathway for cancer treatment in the past *** this review,we summarized the development of inhibitors targeting the RAS-RAF-MEK-ERK pathway with an emphasis on those used in clinical ***,we discussed the potential combinations of inhibitors that target the RAS-RAF-MEK-ERK signaling pathway and other signaling *** inhibitors targeting the RAS-RAF-MEK-ERK pathway have essentially modified the therapeutic strategy against various cancers and deserve more attention in the current cancerresearchandtreatment.

关键词： Clinical trials Molecular target therapy RAS-RAF-MEK-ERK signaling pathway

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Lymph node regression grading of locally advanced rectal cancer treated with neoadjuvant chemoradiotherapy

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World Journal of Gastrointestinal Oncology 2022年第8期14卷 1429-1445页

作者： Lei He Juan Xiao Ping Zheng Lei Zhong Qian Peng School of Medicine University of Electronic Science and Technology of ChinaChengdu 611731Sichuan ProvinceChina Department of Pathology Sichuan Cancer Hospital&InstituteSichuan Cancer CenterSchool of MedicineUniversity of Electronic Science and Technology of ChinaChengdu 610041Sichuan ProvinceChina Personalized drug therapy Key Laboratory of Sichuan Province Sichuan Academy of Medical Sciences and Sichuan Provincial People’s HospitalChengdu 610072Sichuan ProvinceChina Radiation therapy Center Sichuan Cancer Hospital&InstituteSichuan Cancer CenterSchool of MedicineUniversity of Electronic Science and Technology of ChinaChengdu 610041Sichuan ProvinceChina

Neoadjuvant chemoradiotherapy(nCRT)and total rectal mesenteric excision are the main standards of treatment for locally advanced rectal cancer(LARC).Lymph node regression grade(LRG)is an indicator of prognosis and response to preoperative nCRT based on postsurgical metastatic lymph node *** histopathological findings in metastatic lymph nodes after nCRT include necrosis,hemorrhage,nodular fibrosis,foamy histiocytes,cystic cell reactions,areas of hyalinosis,residual cancer cells,and pools of mucin.A number of LRG systems designed to classify the amount of lymph node regression after nCRT is mainly concerned with the relationship between residual cancer cells and regressive fibrosis and with estimating the number of lymph nodes existing with residual cancer *** offers significant prognostic information,and in most cases,LRG after nCRT correlates with patient *** this review,we describe the systematic classification of LRG after nCRT,patient prognosis,the correlation with tumor regression grade,and the typical histopathological findings of lymph *** work may serve as a reference to help predict the clinical complete response and determine lymph node regression in patients based on preservation strategies,allowing for the formulation of more accurate treatment strategies for LARC patients,which has important clinical significance and scientific value.

关键词： Lymph node regression grade Histopathological Rectal cancer Chemoradiotherapy Treatment response Neoadjuvant therapy

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