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Systematic analysis of DNA polymerases as therapeutic targets in pan-cancers

BIOCELL 2024年第1期48卷 123-138页

作者： ZHENHUA LI HUILAI LV FAN ZHANG ZIMING ZHU QIANG GUO MINGBO WANG CHAO HUANG LIJUAN CHEN WENPAN ZHANG YUN LI ZIQIANG TIAN Department of Thoracic Surgery Fourth Hospital of Hebei Medical UniversityShijiazhuang050011China Department of Thoracic Surgery The First Hospital of XingtaiXingtai054001China Department of Thoracic Surgery Affiliated Hospital of Hebei UniversityBaoding050017China Shanghai origimed co. Ltd.Shanghai200000China Department of Thoracic Surgery The Seventh Affiliated Hospital of Sun Yat-sen UniversityShenzhen518107China

Introduction:DNA polymerases are crucial for maintaining genome stability and influencing ***,the clinical implications of DNA polymerases in tumorigenesis and their potential as anti-cancer therapy targets are not well ***:We conducted a systematic analysis using TCGA Pan-Cancer Atlas data and Gene Set Cancer Analysis results to examine the expression profiles of 15 DNA polymerases(POLYs)and their clinical *** also evaluated the prognostic value of POLYs by analyzing their expression levels in relation to overall survival time(OS)using Kaplan-Meier survival ***,we investigated the correlations between POLY expression and immune cells,DNA damage repair(DDR)pathways,and *** sensitivity analysis was performed to assess the relationship between POLY expression and drug ***:Our analysis revealed that 14 out of 15 POLYs exhibited significantly distinct expression patterns between tumor and normal samples across most cancer types,except for DNA nucleotidylexotransferase(DNTT).Specifically,POLD1 and POLE showed elevated expression in almost all cancers,while POLQ exhibited high expression levels in all cancer *** POLYs showed heightened expression in specific cancer subtypes,while others exhibited low ***-Meier survival curves demonstrated significant prognostic value of POLYs in multiple cancers,including PAAD,KIRC,and *** analysis further validated these *** patterns of POLYs varied significantly among different cancer types and were associated with poorer survival *** correlations were observed between the expression of POLY members and immune cells,DDR pathways,and *** sensitivity analysis indicated an inverse relationship between POLY expression and drug ***:Our comprehensive study highlights the significant role of POLYs in cancer development and identifies them as promising prognostic and

关键词： DNA polymerases(POLYs) Prognostic biomarker The Cancer Genome Atlas(TCGA) Ubiquitination network

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First-line camrelizumab(a PD-1 inhibitor)plus apatinib(an VEGFR-2 inhibitor)and chemotherapy for advanced gastric cancer(SPACE):a phase 1 study

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Signal Transduction and Targeted Therapy 2024年第4期9卷 1760-1767页

作者： Xiaofeng Chen Hao Xu Xiaobing Chen Tongpeng Xu Yitong Tian Deqiang Wang Fen Guo Kangxin Wang Guangfu Jin Xiao Li Rong Wang Fengyuan Li Yongbin Ding Jie Tang Yueyu Fang Jing Zhao Liang Liu Ling Ma Lijuan Meng Zhiguo Hou Rongrong Zheng Yang Liu Ni Guan Bei Zhang Shuang Tong Shiqing Chen Xing Li Yongqian Shu Department of Oncology The First Affiliated Hospital with Nanjing Medical UniversityNanjingChina Gusu School Nanjing medical UniversitySuzhouChina Jiangsu Key Lab of Cancer Biomarkers Prevention and TreatmentCollaborative Innovation Center for Cancer Personalized MedicineNanjing Medical UniversityNanjingChina Department of General surgery The First Affiliated Hospital with Nanjing Medical UniversityNanjingChina Department of Oncology Henan Cancer Hospital Affiliated Cancer Hospital of Zhengzhou UniversityZhengzhouChina Henan Engineering Research Center of Precision Therapy of Gastrointestinal Cancer&Zhengzhou Key Laboratory for Precision Therapy of Gastrointestinal Cancer ZhengzhouChina Department of Oncology Digestive Disease Institute&Cancer Institute of Jiangsu UniversityAffiliated Hospital of Jiangsu UniversityZhenjiangChina Department of Oncology Suzhou Hospital of Nanjing Medical UniversitySuzhouChina Department of Oncology Nanjing PuKou People’s HospitalNanjingChina Department of Epidemiology School of Public HealthNanjing Medical UniversityNanjingChina Department of Pathology The First Affiliated Hospital with Nanjing Medical UniversityNanjingChina Department of general surgery Jurong Branch hospital of Jiangsu Province People HospitalJurongChina Department of Medical Oncology Liyang People’s HospitalLiyangChina Department of radiology Nanjing PuKou People’s HospitalNanjingChina Jiangsu Hengrui Pharmaceuticals ShanghaiChina Department of Medical Affairs 3D Medicines Inc.ShanghaiChina Shanghai origimed co. Ltd.ShanghaiChina

Patients with advanced gastric cancer typically face a grim *** phase 1a(dose escalation)and phase 1b(dose expansion)study investigated safety and efficacy of first-line camrelizumab plus apatinib and chemotherapyfor advanced gastric or gastroesophageal junction *** primary endpoints included maximum tolerated dose(MTD)in phase 1a and objective response rate(ORR)across phase 1a and *** 1a tested three dose regimens of camrelizumab,apatinib,oxaliplatin,and *** regimen 1:camrelizumab 200 mg on day 1,apatinib 250 mg every other day,oxaliplatin 100 mg/m^(2) on day 1,and S-140 mg twice a day on days *** regimen 2:same as dose regimen 1,but oxaliplatin 130mg/*** regimen3:same as dose regimen 2,but apatinib 250 mg ***-four patients were included(9 in phase 1a,25 in phase 1b).No dose-limiting toxicities occurred so no MTD was *** 3 was set for the recommended phase 2 doses and administered in phase *** confrmed ORR was 76.5%(95%CI 58.8-89.3).The median progression-free survival was 8.4 months(95%CI 5.9-not evaluable[NE]),and the median overall survival(OS)was not mature(11.6-NE).Ten patients underwent surgery after treatment and the multidisciplinary team *** 24 patients without surgery,the median OS was 19.6 months(7.8-NE).Eighteen patients(52.9%)developed grade≥3 treatment-emergent adverse *** plus apatinib and chemotherapy showed favorable clinical outcomes and manageable safety for untreated advanced gastric cancer(ChiCTR2000034109).

关键词： regimen cancer doses

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Genomic profiling and the impact of MUC19 mutation in hepatoid adenocarcinoma of the stomach

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Cancer communications 2022年第10期42卷 1032-1035页

作者： Mengxuan Zhu Erbao Chen Shan Yu Chen Xu Yiyi Yu Xin Cao Wei Li Pengfei Zhang Yan Wang Baofeng Lian Shuirong Zhang Yueting Qu Lujia Huang Weiwei Shi Yuehong Cui Li Qian Tianshu Liu Department of Medical Oncology Zhongshan HospitalFudan UniversityShanghai 20032P.R.China Center of Evidence-based medicine Fudan UniversityShanghai 20032P.R.China Hepato-Pancreato-Biliary Surgery Peking University Shenzhen HospitalShenzhenGuangdong 518036P.R.China Department of Pathology Zhongshan HospitalFudan UniversityShanghai 20032P.R.China Institute of Clinical Science Zhongshan HospitalFudan UniversityShanghai 20032P.R.China origimed co.ltd Shanghai 20032P.R.China Cancer center Zhongshan hospitalFudan UniversityShanghai 20032P.R.China

Dear Editor,Hepatoid adenocarcinoma(HAC)is a rare pathological subtype of extrahepatic tumor,featured by hepatoid differentiation andα-fetoprotein(AFP)-production[1,2].Hepatoid adenocarcinoma of the stomach(HAS),accounting for 0.3%to 1.0%of all gastric cancers(GCs),has attracted increasing attention due to its high degree of malignancy[3].compared with classic GC,HAS showed a higher rate of vascular invasion,lymph node metastasis,and liver metastasis,with only 9.0%survival rate at 5 years[4].Currently,there is no effective treatment for HAS,and little is known about its ***,we investigated the molecular features of HAS and identified potential therapeutic targets for HAS.

关键词： stomach adenocarcinoma hepato

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The advanced development of molecular targeted therapy for hepatocellular carcinoma

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Cancer Biology & Medicine 2022年第6期19卷 802-817页

作者： Tao Yan Lingxiang Yu Ning Zhang Caiyun Peng Guodong Su Yi Jing Linzhi Zhang Tong Wu Jiamin Cheng Qian Guo Xiaoliang Shi Yinying Lu comprehensive Liver Cancer Center the 5th Medical Center of Chinese PLA General HospitalBeijing 100039China The Second School of Clinical Medicine Southern Medical UniversityGuangzhou 510515China The Second Department of Hepatobiliary Surgery Senior Department of Hepatologythe 5th Medical Center of Chinese PLA General HospitalBeijing 100039China Shanghai origimed co. Ltd.Shanghai 201112China National Clinical Medical Research Center for Infectious Diseases the 5th Medical Center of Chinese PLA General HospitalBeijing 100039China

Hepatocellular carcinoma(HCC),one of the most common malignant tumors in China,severely threatens the life and health of *** recent years,precision medicine,clinical diagnoses,treatments,and innovative research have led to important breakthroughs in HCC *** discovery of new biomarkers and the promotion of liquid biopsy technologies have greatly facilitated the early diagnosis and treatment of *** in targeted therapy and immunotherapy has provided more choices for precise HCC *** technologies,such as genomics,transcriptomics,and metabolomics,have enabled deeper understanding of the occurrence and development mechanisms,heterogeneity,and genetic mutation characteristics of *** continued promotion and accurate typing of HCC,accurate guidance of treatment,and accurate prognostication have provided more treatment opportunities and prolonged survival timelines for patients with *** HCC research providing an in-depth understanding of the biological characteristics of HCC will be translated into accurate clinical practices for the diagnosis and treatment of HCC.

关键词： Hepatocellular carci no ma precision medicine liquid biopsy targeted therapy immunotherapy

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Toripalimab in advanced biliary tract cancer

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The Innovation 2022年第4期3卷 83-89页

作者： Wei Li Yueqi Wang Yiyi Yu Qian Li Yan Wang Chenlu Zhang Xiaojing Xu Xi Guo Yu Dong Yuehong Cui Qing Hao Lujia Huang Houbao Liu Tianshu Liu Department of Oncology Zhongshan HospitalFudan UniversityShanghai 200032China Department of General Surgery Zhongshan HospitalFudan UniversityShanghai 200032China Department of Medicine Shanghai OrigiMed Co.Ltd.Shanghai 201114China Center of Evidence-Based Medicine Fudan UniversityShanghai 200032China

Gemcitabine combined with platinum/fluorouracil drugs is the standard firstline treatment for advanced biliary tract cancers(BTCs).We explored the safety and efficacy of toripalimab plus gemcitabine and S-1(GS)as the first-line treatment for advanced *** a one-sided significance level of 0.025,a total of 50 patients could provide 80%power to show the efficacy at targeted progression-free survival(PFS)rate at 6 months of 70%versus 40%for the combined *** single-arm,phase II study enrolled 50 patients with advanced BTCs who previously received no systemic *** regimen was as follows:toripalimab(240 mg,i.v.,d1),gemcitabine(1,000 mg/m2,i.v.,d1 and d8),and S-1(40–60 mg bid p.o.,d1–14,Q21d).The primary endpoint was progression-free *** secondary endpoints included overall survival(OS),objective response rate(ORR),duration of response(DOR),and *** associations between response with PDL1 expression,tumor mutational burden(TMB),and genetic variations were *** were enrolled from January 2019 to August 2020,with a median follow-up time of 24.0 months(IQR:4.3–31.0 months).

关键词： PDL1 drugs sided

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Loss of chromosome 9p21 is associated with a poor prognosis in adenosquamous carcinoma of the pancreas

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Precision Clinical Medicine 2023年第4期6卷 226-238页

作者： Yina Jiang Yinying Wu Liwen Zhang Yan Wang Guiping Xu Yuan Deng Liang Han Enxiao Li Qingyong Ma Mian Xu Zheng Wu Zheng Wang Department of Pathology The First Affiliated Hospital of Xi’an Jiaotong UniversityXi’an 70061China Pancreatic disease treatment center Xi’an Jiaotong UniversityXi’an 70061China Department of Medical Oncology The First Affiliated Hospital of Xi’an Jiaotong UniversityXi’an 70061China origimed co.ltd Shanghai 201114China Department of Radiology The First Affiliated Hospital of Xi’an Jiaotong UniversityXi’an 70061China Department of Hepatobiliary Surgery The First Affiliated Hospital of Xi’an Jiaotong UniversityXi’an 70061China

Adenosquamous carcinoma of the pancreas(ASCP)is a rare histological subtype of pancreatic cancer with a poor prognosis and a high metastasis ***,little is known about its genomic landscape and prognostic biomarkers.A total of 48 ASCP specimens and 98 pancreatic ductal adenocarcinoma(PDAC)tumour specimens were sequenced to explore the genomic landscape and prognostic *** homozygous deletion of the 9p21.3 region(including CDKN2A,CDKN2B,and MTAP)(9p21 loss)occurred in both ASCP and PDAC,and a higher frequency of 9p21 loss was observed in ASCP(12.5%vs 2.0%,P=0.022).Notably,9p21 loss was significantly associated with poor disease-free survival(DFS)in ASCP patients(mDFS(Median DFS)=4.17 vs 7.33 months,HR(Hazard Ratio)=3.70,P=0.009).The most common gene alterations in patients with ASCP were KRAS(96%),TP53(81%),CDKN2A(42%),SMAD4(21%),CDKN2B(13%),and FAT3(13%).The mutation rates of ACVR2A(6.25%vs 0%),FANCA(6.25%vs 0%),RBM10(6.25%vs 0%),and SPTA1(8.33%vs 1.02%)were significantly higher in ASCP than in *** conclusion,we have comprehensively described the genomic landscape of the largest cohort of ASCP patients to date and highlight that 9p21 loss may be a promising prognostic biomarker for ASCP,which provides a molecular basis for prognosis prediction and new therapeutic strategies for ASCP.

关键词： adenosquamous carcinoma of the pancreas genomic pattern 9p21 loss biomarker prognostic

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Personalized treatment based on mini patient-derived xenografts and WES/RNA sequencing in a patient with metastatic duodenal adenocarcinoma

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Cancer communications 2018年第1期38卷 586-592页

作者： Peng Zhao Hui Chen Danyi Wen Shuo Mou Feifei Zhang Shusen Zheng Cancer Biotherapy Center The First Affiliated Hospital of Zhejiang University School of MedicineHangzhou 310003P.R.China Department of General Surgery Zhejiang HospitalHangzhou 310013P.R.China LIDE Biotech co. LtdShanghaiP.R.China origimed co. LtdShanghaiP.R.China Division of Hepatobiliary and Pancreatic Surgery Department of SurgeryThe First Affiliated Hospital of Zhejiang University School of MedicineHangzhou 310003P.R.China Key Lab of combined Multi-Organ Transplantation Ministry of Public HealthHangzhouChina

Background:Treatment guidelines for a variety of cancers have been increasingly used in clinical practice,and have resulted in major improvement in patient ***,recommended regimens(even first-line treat-ments)are clearly not ideal for every *** the present study,we used mini patient-derived xenograft(mini-PDX)and next-generation sequencing to develop personalized treatment in a patient with metastatic duodenal ***:Resected metachronous metastatic tumor tissues were implanted into SCID mice to determine the sensitivity to a variety of drug *** profiles were assessed using both DNA whole-exome sequencing(DNA-WES)and RNA *** results of the analyses were used to select optimal treatment for the patient with metastatic duodenal ***:Assessment with mini-PDX models took only 7 *** results showed high sensitivity to S-1 plus cis-platin,gemcitabine plus cisplatin and everolimus *** patient received gemcitabine plus cisplatin initially,but the treatment was terminated due to *** patient was then switched to treatment with S-1 *** overall disease-free survival was 34 ***-WES and RNA sequencing identified KRAS mutation(A146T),TP53(C229Yfs*10)and RICTOR amplification in the metastatic duodenal *** findings provided further support to the results of the mini-PDX,and suggest mTOR inhibitors should be used if and when relapse eventually occurs in this ***:Mini-PDX model combined with WES/RNA sequencing can rapidly assess drug sensitivity in cancer patients and reveal key genetic *** research on this technology for personalized therapy in patients with refractory malignant tumors is warranted.

关键词： Duodenal adenocarcinoma Mini patient-derived xenograft Whole-exome sequencing RNA sequencing Somatic mutation Personalized therapy

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Somatic genetic aberrations in gallbladder cancer: comparison between Chinese and US patients

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Hepatobiliary Surgery and Nutrition 2019年第6期8卷 604-614页

作者： Pingzhou Yang Milind Javle Fei Pang Wei Zhao Reham Abdel-Wahab Xiaofeng Chen Funda Meric-Bernstam Huanwei Chen Mitesh JBorad Yu Liu Chuntao Zou Shuo Mu Yutong Xing Kai Wang Chuang Peng Xu Che Department of Hepatobiliary Surgery/Hunan Research Center of Biliary Disease Hunan Provincial People’s Hospital/The First Affiliated Hospital of Hunan Normal UniversityChangsha 410005China Department of Gastrointestinal Medical Oncology The University of Texas MD Anderson Cancer CenterHoustonTXUSA origimed Inc. Shanghai 201114China Department of Hepatobiliary Surgery The Affiliated Hospital of Qingdao UniversityQingdao 266024China Department of Clinical Oncology Assiut University HospitalsAssiutEgypt Department of Oncology The Affiliated Hospital of Nanjing Medical UniversityNanjing 210000China Investigational Cancer Therapeutics The University of Texas MD Anderson Cancer CenterHoustonTXUSA Department of Liver surgery First People’s Hospital of FoshanFoshan 528314China Division of Hematology and Oncology Mayo ClinicScottsdaleAZUSA Department of Pathology People’s Hospital of Hunan ProvinceChangsha 410005China National Cancer Center/National Clinical Research Center for Cancer/Department of Pancreatic and Gastric Surgery Cancer HospitalChinese Academy of Medical Sciences and Peking Union Medical College/National Cancer Center/National Clinical Research Center for Cancer/Department of Hepatobiliary and Pancreatic SurgeryCancer Hospital&Shenzhen HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeShenzhen 518116China

Background:Gallbladder cancer(GBC)is often diagnosed at an advanced stage with limited therapeutic options and poor *** five-year survival rate of this cancer when diagnosed at an advanced stage is below 5%,and the median survival time is less than a year with standard gemcitabine-based *** benefit with second-line treatment is ***,there is an urgent need for novel treatment strategies and targeted therapy based on next generation sequencing(NGS)may be of ***:comprehensive genomic profiling(CGP)was performed with NGS panel on paraffin-embedded tumors from a cohort of 108 Chinese and 107 US GBC *** data were collected using an IRB approved protocol from a single-center in US and from ***:In Chinese and US GBC cohorts,an average of 6.4 vs.3.8 genomic alterations(GAs)were identified per *** most frequent alterations were TP53(69.4%),CDKN2A/B(26%),ERBB2(18.5%),PIK3CA(17%)and CCNE1(13%)in Chinese cohort,TP53(57.9%),CDKN2A/B(25%),SMAD4(17%),ARID1A(14%),PIK3CA(14%)and ERBB2(13.1%)in US ***2L2 mutations were present in 6.5%of Chinese patients and not observed in the US ***,ERBB2 genetic aberrations were significantly associated with better pathological tumor differentiation and tended to co-occurrence with CDKN2A/B mutations in both the Chinese and US GBC *** of the top 9 dysregulated genetic pathways in cancer,Chinese patients harbored more frequent mutations in ERBB genes(30.6%vs.19.0%,P=0.04).High frequency of PI3K/mTOR pathway variations was observed in both Chinese(37%)and US cohort(33%)(P=0.5).Additionally,both Chinese and US GBC patients exhibited a relatively high tumor mutational burden(TMB)(17.6%and 17.0%,respectively).In the Chinese cohort,a significant association was seen between direct repair gene alterations and TMB≥10 muts/Mb(P=0.004).conclusions:In our study,over 83%Chinese and 68%US GBC patients had actionable alterations that could potentially gu

关键词： Gallbladder cancer(GBC) comprehensive genomic profiling(CGP) ERBB2 CDKN2A/B PI3K/mTOR

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