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Antithetical impacts of deleterious LRP1B mutations in non-squamous and squamous NSCLCs on predicting benefits from immune checkpoint inhibitor alone or with chemotherapy over chemotherapy alone: retrospective analyses of the POPLAR/OAK and CHOICE-01 trial

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Science China Life Sciences 2025年第1期 249-262页

作者： Jinliang Wang Wenyong Zhou Yu Xu Jianchun Duan Qiaoxia Zhou Guoqiang Wang Leo Li Chunwei Xu Wenxian Wang Shangli Cai Zhijie Wang Jie Wang Department of oncology The Fifth Medical Center of Chinese PLA General Hospital Department of Thoracic Surgery Shanghai Chest HospitalSchool of MedicineShanghai Jiao Tong University Burning Rock Biotech CAMS Key laboratory of Translational Research on Lung Cancer State Key Laboratory of Molecular OncologyDepartment of Medical OncologyNational Cancer Center/National Clinical Research Center for ancer/Cancer HospitalChinese Academy of Medical Sciences and Peking Union Medical College Institute of Basic Medicine and Cancer (IBMC) Chinese Academy of Sciences Department of Clinical Trial The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital)

In non-small cell lung cancers,the non-squamous and squamous subtypes（nsqNSCLC and sqNSCLC） exhibit disparities in pathophysiology,tumor immunology,and potential genomic correlates affecting responses to immune checkpoint inhibitor（ICI）-based *** our inhouse training cohort（n=85）,the presence of the LRP1B deleterious mutation（LRP1B-del） was associated with longer and shorter progression-free survival（PFS） on ICIs alone in nsqNSCLCs and sqNSCLCs,respectively(Pinteraction=0.008).These results were validated using a larger public ICI cohort(n=208,Pinteraction<0.001).Multiplex immunofluorescence staining revealed an association between LRP1B-del and increased and decreased numbers of tumor-infiltrating CD8+T cells in nsqNSCLCs（P=0.040） and sqNSCLCs（P=0.014）,*** the POPLAR/OAK cohort,nsqNSCLCs with LRP1B-del demonstrated improved PFS benefits from atezolizumab over docetaxel(hazard ratio（HR）=0.70,P=0.046),whereas this benefit was negligible in those without LRP1B-del（HR=1.05,P=0.64）.Conversely,sqNSCLCs without LRP1B-del benefited more from atezolizumab（HR=0.60,P=0.002） than those with LRP1B-del（HR=1.30,P=0.31）.Consistent results were observed in the in-house CHOICE-01 cohort,in which nsqNSCLCs with LRP1B-del and sqNSCLCs without LRP1B-del benefited more from toripalimab plus chemotherapy than from chemotherapy alone(Pinteraction=0.008).This multi-cohort study delineates the antithetical impacts of LRP1B-del in nsqNSCLCs and sqNSCLCs on predicting the benefits from ICI alone or with chemotherapy over chemotherapy *** findings highlight the distinct clinical utility of LRP1B-del in guiding treatment choices for nsqNSCLCs and sqNSCLCs,emphasizing the necessity for a detailed analysis based on pathological subtypes when investigating biomarkers for cancer therapeutics.

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Copper-catalyzed C–H bond functionalization enabled by programmed alternating current

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Science China Chemistry 2025年第1期 10-11页

作者： Zhoumei Tan Kun Xu Chengchu Zeng Beijing Key laboratory of Environmental and Viral oncology College of Chemistry and Life Science Beijing University of Technology

Synthetic electrochemistry has been selected as one of the Top Ten Emerging Technologies in Chemistry in 2023 by International Union of Pure and Applied Chemistry (IUPAC)[1]. It has emerged as a sustainable platform for organic synthesis and has exhibited a wide range of applications from academia to industry [2]. However, electrosynthesis has been predominantly performed by using direct current (DC).

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AZD1775 synergizes with SLC7A11 inhibition to promote ferroptosis

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Science China Life Sciences 2025年第1期 204-218页

作者： Chen Xiong Hong Ling Yingdan Huang Hanzhi Dong Bangxiang Xie Qian Hao Xiang Zhou Fudan University Shanghai Cancer Center and Institutes of Biomedical Sciences Fudan University Department of oncology Shanghai Medical CollegeFudan University Department of Breast Surgery Fudan University Shanghai Cancer CenterFudan University Department of oncology First Affiliated Hospital of Nanchang University Beijing Institute of Hepatology Beijing Youan HospitalCapital Medical University Beijing Engineering Research Center for Precision Medicine and Transformation of Hepatitis and Liver Cancer Key laboratory of Breast Cancer in Shanghai Fudan University Shanghai Cancer CenterFudan University Shanghai Key laboratory of medical Epigenetics International Co-laboratory of Medical Epigenetics and Metabolism (Ministry of Science and Technology)Institutes of Biomedical SciencesFudan University

Tumor suppressor p53-mediated cell cycle arrest and DNA damage repair may exert cytoprotective effects against cancer therapies, including WEE1 inhibition. Considering that p53 activation can also lead to multiple types of cell death, the role of this tumor suppressor in WEE1 inhibitor-based therapies remains disputed. In this study, we reported that nucleolar stress-mediated p53 activation enhanced the WEE1 inhibitor AZD1775-induced ferroptosis to suppress lung cancer growth. Our findings showed that AZD1775 promoted ferroptosis by blocking cystine uptake, an action similar to that of Erastin. Meanwhile, inhibition of WEE1 by the WEE1 inhibitors or si RNAs induced compensatory upregulation of SLC7A11, which conferred resistance to ferroptosis. Mechanistically, AZD1775 prevented the enrichment of H3K9me3, a histone marker of transcriptional repression, on the SLC7A11 promoter by repressing the expression of the histone methyltransferase SETDB1, thereby enhancing NRF2-mediated SLC7A11 transcription. This finding was also validated using the H3K9me3 inhibitor BRD4770. Remarkably, we found that the nucleolar stress-inducing agent Actinomycin D(Act. D) inhibited SLC7A11 expression by activating p53, thus augmenting AZD1775-induced ferroptosis. Moreover, the combination of AZD1775 and Act. D synergistically suppressed wild-type p53-harboring lung cancer cell growth both in vitro and in vivo. Altogether, our study demonstrates that AZD1775 promotes ferroptosis by targeting cystine uptake but also mediates the adaptive activation of SLC7A11 through the WEE1-SETDB1 cascade and NRF2-induced transcription, and inhibition of SLC7A11 by Act. D boosts the anti-tumor efficacy of AZD1775 by enhancing ferroptosis in cancers with wild-type p53.

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AAV mediated carboxyl terminus of Hsp70 interacting protein overexpression mitigates the cognitive and pathological phenotypes of APP/PS1 mice

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Neural Regeneration Research 2025年第1期20卷 253-264页

作者： Zhengwei Hu Jing Yang Shuo Zhang Mengjie Li Chunyan Zuo Chengyuan Mao Zhongxian Zhang Mibo Tang Changhe Shi Yuming Xu Department of Neurology The First Affiliated Hospital of Zhengzhou UniversityZhengzhou UniversityZhengzhouHenan ProvinceChina Academy of medical Sciences of Zhengzhou University ZhengzhouHenan ProvinceChina NHC Key laboratory of Prevention and treatment of Cerebrovascular Diseases The First Affiliated Hospital of Zhengzhou UniversityZhengzhou UniversityZhengzhouHenan ProvinceChina Henan Key laboratory of Cerebrovascular Diseases The First Affiliated Hospital of Zhengzhou UniversityZhengzhou UniversityZhengzhouHenan ProvinceChina Institute of Neuroscience Zhengzhou UniversityZhengzhouHenan ProvinceChina Sino-British Research Centre for Molecular oncology National Centre for International Research in Cell and Gene TherapySchool of Basic Medical SciencesAcademy of Medical SciencesZhengzhou UniversityZhengzhouHenan ProvinceChina Department of Gerontology The First Affiliated Hospital of Zhengzhou UniversityZhengzhou UniversityZhengzhouHenan ProvinceChina

The E3 ubiquitin ligase,carboxyl terminus of heat shock protein 70(Hsp70)interacting protein(CHIP),also functions as a co-chaperone and plays a crucial role in the protein quality control *** this study,we aimed to investigate the neuroprotective effect of overexpressed CHIP on Alzheimer’s *** used an adeno-associated virus vector that can cross the blood-brain barrier to mediate CHIP overexpression in APP/PS1 mouse *** overexpression significantly ameliorated the performance of APP/PS1 mice in the Morris water maze and nest building tests,reduced amyloid-βplaques,and decreased the expression of both amyloid-βand phosphorylated *** also alleviated the concentration of microglia and astrocytes around *** APP/PS1 mice of a younger age,CHIP overexpression promoted an increase in ADAM10 expression and inhibitedβ-site APP cleaving enzyme 1,insulin degrading enzyme,and neprilysin *** of HSP70 and HSP40,which have functional relevance to CHIP,were also *** nuclei transcriptome sequencing in the hippocampus of CHIP overexpressed mice showed that the lysosomal pathway and oligodendrocyte-related biological processes were up-regulated,which may also reflect a potential mechanism for the neuroprotective effect of *** research shows that CHIP effectively reduces the behavior and pathological manifestations of APP/PS1 ***,overexpression of CHIP could be a beneficial approach for the treatment of Alzheimer’s disease.

关键词： adeno-associated virus Alzheimer’s disease APP/PS1 mice carboxyl terminus of Hsp70 interacting protein gene therapy

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Integration of perioperative features and intragraft TCF7L2 expression to predict lipid metabolic disorder in liver transplant recipients

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Science China Life Sciences 2025年第1期 297-299页

作者： Junbin Zhou Rongli Wei Guanghan Fan Zhengxing Lian Xuanyu Zhang Linsong Tang Zhetuo Qi Haiyang Xie Shusen Zheng Qiang Wei Xiao Xu Department of Hepatobiliary and Pancreatic Surgery People's Hospital of LishuiAffiliated Lishui Hospital of Wenzhou Medical UniversityThe First Affiliated Hospital of Lishui University NHFPC Key laboratory of Combined Multi-Organ Transplantation Key laboratory of Integrated oncology and Intelligent Medicine of Zhejiang Province Department of Hepatobiliary and Pancreatic SurgeryHangzhou First People's Hospital Department of Hepatobiliary and Pancreatic Surgery The First Affiliated HospitalZhejiang University School of Medicine Department of Urology The Second Affiliated HospitalZhejiang University School of Medicine Department of Hepatobiliary and Pancreatic Surgery Department of Liver TransplantationShulan (Hangzhou) Hospital Hangzhou medical College Zhejiang University School of Medicine

Dear Editor, Liver transplantation(LT) is the only curative therapy for patients with endstage liver disease(He et al., 2023; Ling et al., 2022). Post-transplant hypertriglyceridemia(PTHT), which has an incidence of up to 32.8% in 6 months after LT, is one of the major post-transplant complications(Toshima et al., 2020).

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IDENTIFICATION OF DRUG RESISTANT RELATED cDNA IN LUNG ADENOCARCINOMA CELL LINES

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Chinese Journal of Cancer Research 2001年第2期13卷 101-104页

作者：王洁刘叙仪李西平李振甫张宏 Department of medical oncology 2 Center Laboratory School of Oncology Peking University Center laboratory School of Oncology Peking University

Objective: To clone multidrug resistance (MDR) related genes in lung adenocarcinoma cell lines. Methods: The differentially expressed cDNA fragments between A549 and A549 DDP cells were analyzed by mRNA differential display PCR(DD RT-PCR). The fragments thus obtained were further analyzed by DNA sequencing and Northern blotting. Results: Three differentially expressed cDNA fragments were obtained and confirmed by Northern blot. Sequence analysis revealed that two of them were novel and one was 100% identical with ICE gene. Conclusion: Analyzing differentially expressed fragment between A549 and A549 DDP cells may be helpful for finding new MDR related genes. The drug resistance of A549 DDP cells may be related to the inhibition or down-regulation of ICE gene.

关键词： A549 and A549 DDP cells mRNA differential display MDR related gene

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Right-sided colon cancer and left-sided colorectal cancer respond differently to cetuximab

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癌症 2015年第9期34卷 384-393页

作者： Feng Wang Long Bai Tian-Shu Liu Yi-Yi Yu Ming-Ming He Kai-Yan Liu Hui-Yan Luo Dong-Sheng Zhang Yin Jin Feng-Hua Wang Zhi-Qiang Wang De-Shen Wang Miao-Zhen Qiu Chao Ren Yu-Hong Li Rui-Hua Xu Department of medical oncology Sun Yat-sen University Cancer Center:State Key Laboratory of Oncology in South China Department of medical oncology Zhongshan HospitalFudan University Collaborative Innovation Center for Cancer Medicine

Introduction: Right-sided colon cancer(RSCC) and left-sided colorectal cancer(LSCRC) differ with respect to their biology and genomic patterns. This study aimed to examine whether the primary tumor location is associated with the response to cetuximab in patients with metastatic colorectal cancer(m CRC).Methods: Patients with mC RC treated with cetuximab and standard chemotherapy as first- or second-line treatments were compared with randomly chosen patients who were treated with chemotherapy alone between 2005 and *** main outcome measures were the overal response rate(ORR), progression-free survival(PFS), and overal survival(OS).The differences in the outcome were analyzed by using the chi-squared test, Student’s t test, and Kaplan-Meier ***: The treatment results of 206 patients with m CRC treated with cetuximab and standard chemotherapy as first- or second-line treatments were compared with those of 210 patients who were treated with chemotherapy alone. As a first-line treatment, cetuximab with chemotherapy was associated with a significantly higher ORR(49.4 % vs. 28.6 %, P = 0.005) as well as longer PFS(9.1 vs. 6.2 months, P = 0.002) and OS(28.9 vs. 20.1 months,P = 0.036) than chemotherapy alone in patients with LSCRC. However, cetuximab neither improved the ORR(36.4 % vs. 26.2 %, P = 0.349) nor prolonged PFS(5.6 vs. 5.7 months, P = 0.904) or OS(25.1 vs. 19.8 months, P = 0.553) in patients with RSCC. As a second-line treatment, cetuximab exhibited a tendency to improve the ORR(23.5 % vs. 10.2 %,P = 0.087) and prolong PFS(4.9 vs. 3.5 months, P = 0.064), and it significantly prolonged OS(17.1 vs. 12.4 months,P = 0.047) compared with chemotherapy alone in the patients with LSCRC. In contrast, as a second-line treatment,cetuximab neither improved the ORR(7.1 % vs. 11.4 %, P = 0.698) nor prolonged PFS(3.3 vs. 4.2 months, P = 0.761) or OS(13.4 vs. 13.0 months, P = 0.652) in patients with ***: The addition of cetuximab to chemotherapy in b

关键词： Colorectal neoplasms Cetuximab Left-sided Right-sided Chemotherapy

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Cloning of a novel cDNA regulated by all-trans retinoic acid in human lung adenocarcinoma

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Progress in Natural Science:Materials International 1999年第10期9卷 3-5页

作者：刘桂中,刘芝华,Giovanni LEVI,吴旻 State Key laboratory of Molecular oncology Cancer Institute Chinese Academy of medical Sciences & Peking Union medical College Beijing 100021 China State Key laboratory of Molecular oncology Cancer Institute Chinese Academy of medical Sciences & Peking Union medical College Beijing 100021 China laboratory of Molecular Biology National Institute for Cancer Research Genova Italy State Key laboratory of Molecular oncology Cancer Institute Chinese Academy of medical Sciences & Peking Union medical College Beijing 100021 China

To characterize genes associated with differentiation/apoptosis induced by all- trans retinoic acid (ATRA) in human lung cancer cells, the mRNA differential display was employed and a cDNA fragment RAa7 was obtained which is up-regulated by ATRA. Search for homologous sequences in GenBank databases demonstrates that RAa7 is a novel sequence which has never been reported. Here evidence is provided that the RAa7 gene may be a tissue-specific expressing gene and has a major transcript of 1.4 kb. RAa7 gene is down-regulated during differentiation or apoptosis in several other kinds of lung cancer cells induced by ATRA and N- (4-hydroxyphenyl) retinamide (4HPR) . This suggests that either the up- or down-regulation of RAa7 gene may be involved in the processes of cell differentiation or apoptosis.

关键词： mRNA differential display retinoic acids cell differentiation apoptosis cancer

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Adjuvant chemotherapy,p53,carcinoembryonic antigen expression and prognosis after D2 gastrectomy for gastric adenocarcinoma

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World Journal of Gastroenterology 2014年第1期20卷 264-273页

作者： Ming-Ming He Dong-Sheng Zhang Feng Wang Zhi-Qiang Wang Hui-Yan Luo Chao Ren Ying Jin Dong-Liang Chen Rui-Hua Xu State Key laboratory of oncology in South China Department of Medical OncologySun Yat-sen University Cancer Center

AIM: To investigate adjuvant chemotherapy, p53 and carcinoembryonic antigen (CEA) expression and prognosis after D2 gastrectomy for stage II/III gastric adenocarcinoma.

关键词： Gastric adenocarcinoma Adjuvant chemotherapy p53 Carcinoembryonic antigen Immunohistochemistry

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The novel ER stress inducer Sec C triggers apoptosis by sulfating ER cysteine residues and degrading YAP via ER stress in pancreatic cancer cells

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Acta Pharmaceutica Sinica B 2022年第1期12卷 210-227页

作者： Junxia Wang Minghua Chen Mengyan Wang Wenxia Zhao Conghui Zhang Xiujun Liu Meilian Cai Yuhan Qiu Tianshu Zhang Huimin Zhou Wuli Zhao Shuyi Si Rongguang Shao Key laboratory of Antibiotic Bioengineering Ministry of HealthLaboratory of OncologyInstitute of Medicinal BiotechnologyChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100050China

Pancreatic adenocarcinoma(PAAD) is one of the most lethal malignancies. Although gemcitabine(GEM) is a standard treatment for PAAD, resistance limits its application and therapy. Secoemestrin C(Sec C) is a natural compound from the endophytic fungus Emericella, and its anticancer activity has not been investigated since it was isolated. Our research is the first to indicate that Sec C is a broad-spectrum anticancer agent and could exhibit potently similar anticancer activity both in GEM-resistant and GEM-sensitive PAAD cells. Interestingly, Sec C exerted a rapid growth-inhibiting effect(80% death at 6 h), which might be beneficial for patients who need rapid tumor shrinkage before surgery. Liquid chromatography/mass spectrometry and N-acetyl-L-cysteine(NAC) reverse assays show that Sec C sulfates cysteines to disrupt disulfide-bonds formation in endoplasmic reticulum(ER) proteins to cause protein misfolding, leading to ER stress and disorder of lipid biosynthesis. Microarray data and subsequent assays show that ER stress-mediated ER-associated degradation(ERAD) ubiquitinates anddownregulates YAP to enhance ER stress via destruction complex(YAP-Axin-GSK-βTr CP), which also elucidates a unique degrading style for YAP. Potent anticancer activity in GEM-resistant cells and low toxicity make Sec C a promising anti-PAAD candidate.

关键词： Pancreatic cancer Secoemestrin C YAP degradation ER stress inducer Resistance Fast shrinkage YAP destruction complex Lipid droplet formation

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