检索结果-内蒙古大学图书馆

Targeting protein-protein interaction interfaces with antiviral N protein inhibitor in SARS-CoV-2

Biophysical Journal 2024年第4期123卷 478-488页

作者： Hong, Jhen-Yi Lin, Shih-Chao Kehn-Hall, Kylene Zhang, Kai-Min Luo, Shun-Yuan Wu, Hung-Yi Chang, Sui-Yuan Hou, Ming-Hon Institute of Genomics and Bioinformatics and Department of Life Sciences National Chung Hsing University Taichung Taiwan Bachelor Degree Program in Marine Biotechnology College of Life Sciences National Taiwan Ocean University Keelung Taiwan Department of Biomedical Sciences and Pathobiology Virginia-Maryland College of Veterinary Medicine Virginia Polytechnic Institute and State University Blacksburg VA United States Center for Emerging Zoonotic and Arthropod-borne Pathogens Virginia Polytechnic Institute and State University Blacksburg VA United States Department of Chemistry National Chung Hsing University Taichung Taiwan Graduate Institute of Veterinary Pathobiology College of Veterinary Medicine National Chung Hsing University. Taichung Taiwan Department of Clinical Laboratory Sciences and Medical Biotechnology College of Medicine National Taiwan University Taipei Taiwan PhD Program in Medical Biotechnology National Chung Hsing University Taichung Taiwan Biotechnology Center National Chung Hsing University Taichung Taiwan

Coronaviruses not only pose significant global public health threats but also cause extensive damage to livestock-based industries. Previous studies have shown that 5-benzyloxygramine (P3) targets the Middle East respiratory syndrome coronavirus (MERS-CoV) nucleocapsid (N) protein N-terminal domain (N-NTD), inducing non-native protein-protein interactions (PPIs) that impair N protein function. Moreover, P3 exhibits broad-spectrum antiviral activity against CoVs. The sequence similarity of N proteins is relatively low among CoVs, further exhibiting notable variations in the hydrophobic residue responsible for non-native PPIs in the N-NTD. Therefore, to ascertain the mechanism by which P3 demonstrates broad-spectrum anti-CoV activity, we determined the crystal structure of the SARS-CoV-2 N-NTD:P3 complex. We found that P3 was positioned in the dimeric N-NTD via hydrophobic contacts. Compared with the interfaces in MERS-CoV N-NTD, P3 had a reversed orientation in SARS-CoV-2 N-NTD. The Phe residue in the MERS-CoV N-NTD:P3 complex stabilized both P3 moieties. However, in the SARS-CoV-2 N-NTD:P3 complex, the Ile residue formed only one interaction with the P3 benzene ring. Moreover, the pocket in the SARS-CoV-2 N-NTD:P3 complex was more hydrophobic, favoring the insertion of the P3 benzene ring into the complex. Nevertheless, hydrophobic interactions remained the primary stabilizing force in both complexes. These findings suggested that despite the differences in the sequence, P3 can accommodate a hydrophobic pocket in N-NTD to mediate a non-native PPI, enabling its effectiveness against various CoVs. © 2024 Biophysical Society

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Metformin escape in prostate cancer by activating the PTGR1 transcriptional program through a novel super-enhancer

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Signal Transduction and Targeted Therapy 2023年第9期8卷 4365-4379页

作者： Jianheng Ye Shanghua Cai Yuanfa Feng Jinchuang Li Zhiduan Cai Yulin Deng Ren Liu Xuejin Zhu Jianming Lu Yangjia Zhuo Yingke Liang Jianjiang Xie Yanqiong Zhang Huichan He Zhaodong Han Zhenyu Jia Weide Zhong Department of Urology Guangzhou First People’s HospitalSouth China University of Technology510180 GuangzhouGuangdongChina Urology Key Laboratory of Guangdong Province The First Affiliated Hospital of Guangzhou Medical UniversityGuangzhou Medical University510230 GuangzhouGuangdongChina Guangzhou National Laboratory No.9 XingDaoHuanBei RoadGuangzhou International Bio Island510005 GuangzhouGuangdongChina Institute of Chinese Materia Medica China Academy of Chinese Medical Sciences100700 BeijingChina Department of Botany and Plant Sciences University of CaliforniaRiversideCA 92507USA Graduate Program in Genetics Genomics&BioinformaticsUniversity of CaliforniaRiversideCA 92507USA State Key Laboratory of Quality Research in Chinese Medicine Macao University of Science and TechnologyTaipa999078 MacaoChina

The therapeutic efficacy of metformin in prostate cancer(PCa)appears uncertain based on various clinical *** treatment failure may be attributed to the high frequency of transcriptional dysregulation,which leads to drug ***,the underlying mechanism is still *** this study,we found evidences that metformin resistance in PCa cells may be linked to cell cycle ***-enhancers(SEs),crucial regulatory elements,have been shown to be associated with drug resistance in various *** analysis of SEs in metformin-resistant(MetR)PCa cells revealed a correlation with Prostaglandin Reductase 1(PTGR1)expression,which was identified as significantly increased in a cluster of cells with metformin resistance through single-cell transcriptome *** functional experiments showed that PTGR1 overexpression accelerated cell cycle progression by promoting progression from the G0/G1 to the S and G2/M phases,resulting in reduced sensitivity to ***,we identified key transcription factors that significantly increase PTGR1 expression,such as SRF and RUNX3,providing potential new targets to address metformin resistance in *** conclusion,our study sheds new light on the cellular mechanism underlying metformin resistance and the regulation of the SE-TFs-PTGR1 axis,offering potential avenues to enhance metformin’s therapeutic efficacy in PCa.

关键词： RUNX3 cancer offering

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BAG6 restricts pancreatic cancer progression by suppressing the release of IL33-presenting extracellular vesicles and the activation of mast cells

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Cellular & Molecular Immunology 2024年第8期21卷 918-931页

作者： Bilal Alashkar Alhamwe Viviane Ponath Fahd Alhamdan Bastian Dörsam Clara Landwehr Manuel Linder Kim Pauck Sarah Miethe Holger Garn Florian Finkernagel Anna Brichkina Matthias Lauth Dinesh Kumar Tiwari Malte Buchholz Daniel Bachurski Sabrina Elmshäuser Andrea Nist Thorsten Stiewe Lisa Pogge von Strandmann Witold Szymański Vanessa Beutgen Johannes Graumann Julia Teply-Szymanski Corinna Keber Carsten Denkert Ralf Jacob Christian Preußer Elke Pogge von Strandmann Institute for Tumor Immunology Philipps-University35043MarburgGermany Core Facility Extracellular Vesicles Philipps-University35043MarburgGermany Department of Anesthesiology Critical Careand Pain MedicineCardiac Anesthesia DivisionBoston Children’s HospitalBostonUSA Department of Immunology and Anaesthesia Harvard Medical SchoolBostonMAUSA Translational Inflammation Research Division&Core Facility for Single Cell Multiomics Philipps-University35043MarburgGermany Core Facility Bioinformatics Philipps-University35043MarburgGermany Clinic for Gastroenterology Endocrinology and MetabolismCenter for Tumor and Immune BiologyPhilipps-University35043MarburgGermany Institute of Systems Immunology Philipps-University35043MarburgGermany Cluster of Excellence on Cellular Stress Responses in Aging-Associated Diseases(CECAD) University of CologneCologneGermany Institute of Molecular Oncology and Genomics Core Facility Member of the German Center for Lung Research(DZL)Philipps-University35043MarburgGermany Institute of Lung Health Justus Liebig University35392GiessenGermany Institute of Translational Proteomics&Core Facility Translational Proteomics Biochemical/Pharmacological CentrePhilipps-University35043MarburgGermany Institute of Pathology Philipps-University Marburg and University Hospital Marburg(UKGM)MarburgGermany Department of Cell Biology and Cell Pathology Philipps-University35043MarburgGermany

Recent studies reveal a critical role of tumor cell-released extracellular vesicles(EVs)in pancreatic cancer(PC)***,driver genes that direct EV function,the EV-recipient cells,and their cellular response to EV uptake remain to be ***,we studied the role of Bcl-2-associated-anthanogene 6(BAG6),a regulator of EV biogenesis for cancer *** used a Cre recombinase/LoxP-based reporter system in combination with single-cell RNA sequencing to monitor in vivo EV uptake and tumor microenvironment(TME)changes in mouse models for pancreatic ductal adenocarcinoma(PDAC)in a Bag6 pro-or deficient *** vivo data were validated using mouse and human organoids and patient *** data demonstrated that Bag6-deficient subcutaneous and orthotopic PDAC tumors accelerated tumor growth dependent on EV ***,this was attributed to mast cell(MC)activation via EV-associated *** MCs promoted tumor cell proliferation and altered the composition of the TME affecting fibroblast polarization and immune cell *** cell proliferation and fibroblast polarization were mediated via the MC secretome containing high levels of PDGF and *** with high BAG6 gene expression and high protein plasma level have a longer overall survival indicating clinical *** current study revealed a so far unknown tumor-suppressing activity of BAG6 in ***6-deficiency allowed the release of EV-associated IL33 which modulate the TME via MC activation promoting aggressive tumor *** depletion using imatinib diminished tumor growth providing a scientific rationale to consider imatinib for patients stratified with low BAG6 expression and high MC infiltration.

关键词： Pancreatic cancer EVs BAG6 Mast cells

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Moving beyond gene expression: identification of lung-disease-associated novel transcripts and alternative splicing by RNA sequencing

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BMC Proceedings 2012年第6期6卷 1-2页

作者： John Brothers II Paola Sebastiani Marc Lenburg Avrum Spira Rebecca Kusko Yuriy Alekesyev Gang Liu Lingqi Luo Jennifer Beane Brenda Juan Guardela John Tedrow Frank Sciurba Naftali Kaminski Ivana V Yang David A Schwartz Mick Correll John Quackenbush Mark Geraci Bioinformatics Program Boston University Boston MA 02115 USA Genetics and Genomics Graduate Program Boston University School of Medicine Boston MA 02118 USA Department of Medicine Boston University School of Medicine Section of Computational Biomedicine Boston MA 02118 USA Department of Pathology and Laboratory Medicine Boston University School of Medicine Boston MA 02118 USA Simmons Center for Interstitial Lung Disease and Department of Medicine University of Pittsburgh Medical Center Pittsburgh PA 15213 USA Center for Genes Environment and Health and Department of Medicine National Jewish Health Denver CO 80206 USA Dana-Farber Cancer Institute and Harvard School of Public Health Boston MA 02115 USA Department of Medicine University of Colorado School of Medicine Aurora CO 80045 USA

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Artificial intelligence-driven genotype–epigenotype–phenotype approaches to resolve challenges in syndrome diagnostics

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eBiomedicine 2025年 115卷 105677-105677页

作者： Mak, Christopher C.Y. Klinkhammer, Hannah Choufani, Sanaa Reko, Nikola Christman, Angela K. Pisan, Elise Chui, Martin M.C. Lee, Mianne Leduc, Fiona Dempsey, Jennifer C. Sanchez-Lara, Pedro A. Bombei, Hannah M. Bernat, John A. Faivre, Laurence Mau-Them, Frederic Tran Palafoll, Irene Valenzuela Canham, Natalie Sarkar, Ajoy Zarate, Yuri A. Callewaert, Bert Bukowska-Olech, Ewelina Jamsheer, Aleksander Zankl, Andreas Willems, Marjolaine Duncan, Laura Isidor, Bertrand Cogne, Benjamin Boute, Odile Vanlerberghe, Clémence Goldenberg, Alice Stolerman, Elliot Low, Karen J. Gilard, Vianney Amiel, Jeanne Lin, Angela E. Gordon, Christopher T. Doherty, Dan Krawitz, Peter M. Weksberg, Rosanna Hsieh, Tzung-Chien Chung, Brian H.Y. Department of Paediatrics and Adolescent Medicine School of Clinical Medicine The University of Hong Kong Hong Kong SAR China Institute for Genomic Statistics and Bioinformatics University Hospital Bonn Rheinische Friedrich-Wilhelms-Universität Bonn Bonn Germany Institute for Medical Biometry Informatics and Epidemiology University Hospital Bonn Rheinische Friedrich-Wilhelms-Universität Bonn Bonn Germany Genetics and Genome Biology Program Research Institute The Hospital for Sick Children Toronto M5G 1X8 ON Canada Department of Pediatrics University of Washington Seattle 98195 WA United States Laboratory of Embryology and Genetics of Human Malformations Institut National de la Santé et de la Recherche Médicale (INSERM) UMR 1163 Institut Imagine Université Paris Cité Paris 75015 France CHU Lille Centre de Référence Anomalies du Développement et Syndromes Malformatifs Lille F-59000 France Department of Pediatrics Cedars-Sinai Medical Center Los Angeles CA United States Division of Medical Genetics and Genomics Stead Family Department of Pediatrics University of Iowa Hospitals Iowa City IA United States Centre de Génétique et Centre de Référence Anomalies du Développement et Syndromes Malformatifs FHU TRANSLAD Institut GIMI Hôpital d'Enfants CHU Dijon-Bourgogne Dijon France Equipe GAD INSERM UMR1231 Université de Bourgogne Franche Comté Dijon France UF 6254 Innovation en diagnostic Génomique des Maladies Rares Centre Hospitalier Universitaire de Dijon Dijon France Department of Clinical and Molecular Genetics University Hospital Vall d'Hebron and Medicine Genetics Group Valle Hebron Research Institute Barcelona Spain Liverpool Centre for Genomic Medicine Liverpool Women's Hospital Crown Street Liverpool United Kingdom Department of Clinical Genetics Nottingham University Hospitals National Health Service Trust Nottingham NG5 1PB United Kingdom Section of Genetics and Metabolism University of Arkansas for Medical Sciences Little Rock 72701 AR Uni

Background: Decisions to split two or more phenotypic manifestations related to genetic variations within the same gene can be challenging, especially during the early stages of syndrome discovery. Genotype-based diagnostics with artificial intelligence (AI)-driven approaches using next-generation phenotyping (NGP) and DNA methylation (DNAm) can be utilized to expedite syndrome delineation within a single gene. Methods: We utilized an expanded cohort of 56 patients (22 previously unpublished individuals) with truncating variants in the MN1 gene and attempted different methods to assess plausible strategies to objectively delineate phenotypic differences between the C-Terminal Truncation (CTT) and N-Terminal Truncation (NTT) groups. This involved transcriptomics analysis on available patient fibroblast samples and AI-assisted approaches, including a new statistical method of GestaltMatcher on facial photos and blood DNAm analysis using a support vector machine (SVM) model. Findings: RNA-seq analysis was unable to show a significant difference in transcript expression despite our previous hypothesis that NTT variants would induce nonsense mediated decay. DNAm analysis on nine blood DNA samples revealed an episignature for the CTT group. In parallel, the new statistical method of GestaltMatcher objectively distinguished the CTT and NTT groups with a low requirement for cohort number. Validation of this approach was performed on syndromes with known DNAm signatures of SRCAP, SMARCA2 and ADNP to demonstrate the effectiveness of this approach. Interpretation: We demonstrate the potential of using AI-based technologies to leverage genotype, phenotype and epigenetics data in facilitating splitting decisions in diagnosis of syndromes with minimal sample requirement. Funding: The specific funding of this article is provided in the acknowledgements section. © 2025 The Authors

关键词： GestaltMatcher MCTT Methylation MN1 Splitting Support vector machine

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The cell surface marker CD36 selectively identifies matured,mitochondria-rich hPSC-cardiomyocytes

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细胞研究（英文版） 2020年第7期30卷 626-629页

作者： Ellen Ngar-Yun Poon Xiao-ling Luo Sarah E.Webb Bin Yan Rui Zhao Stanley Chun Ming Wu Yong Yang Peng Zhang Huajun Bai Jiaofang Shao Ching Man Chan Godfrey Chi-Fung Chan Suk Ying Tsang Rebekah L.Gundry Huang-Tian Yang Kenneth R.Boheler Department of Medicine and Therapeutics and Centre for Cardiovascular Genomics and Medicine The Chinese University of Hong Kong (CUHK) HKSAR China CAS Key Laboratory of Tissue Microenvironment and Tumor Laboratory of Molecular CardiologyShanghai Institute of Nutrition and Health University of Chinese Academy of Sciences (CAS) CAS Shanghai China Division of Life Science and State Key Laboratory of Molecular Neuroscience The Hong Kong University of Science and Technology HKSAR China Department of Computer Science The University of Hong Kong (HKU) HKSAR China Intervention and Cell Therapy Center Peking University Shenzhen Hospital Shenzhen China School of Life Sciences CUHK HKSAR China Department of Paediatrics and Adolescent Medicine HKU HKSAR China School of Biomedical Sciences HKU HKSAR China SUSTech Academy for Advanced Interdisciplinary Studies Southern University of Science and Technology (SUSTech) Shenzhen China Department of Bioinformatics School of Biomedical Engineering and InformaticsNanjing Medical University Nanjing Jiangsu China State Key Laboratory of Agrobiotechnology CUHK HKSAR China Department of Biochemistry and Center for Biomedical Mass Spectrometry Research Medical College of Wisconsin Milwaukee WIUSA CardiOmics Program Center for Heart and Vascular Research Division of Cardiovascular Medicine and Department of Cellular and Integrative Physiology University of Nebraska Medical Center Omaha NE USA Institute for Stem Cell and Regeneration Medicine CASBeijing China Division of Cardiology Department of Medicineand Department of Biomedical Engineering The Johns Hopkins University Baltimore MD USA

Dear Editor,Human pluripotent stem cell (hPSC)-derived cardiomyocytes (CMs) are of significant translational value to in vitro studies of human cardiac development, drug and cardiotoxicity testing and cardiac disease *** of hPSCs to CMs,however, yields mixed cultures of atrial-, ventricular-, and pacemaker-like cells as well as non-CMs in variable proportions.1

关键词： Stem-cell differentiation Stem cells

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Identification of microRNA in the protist Trichomonas vaginalis

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genomics 2009年第5期93卷 487-493页

作者： Lin, Wei-Chen Li, Sung-Chou Lin, Wen-Chang Shin, Jyh-Wei Hu, Song-Nian Yu, Xiao-Min Huang, Ting-Yun Chen, Shih-Chieh Chen, Hua-Chien Chen, Shu-Jen Huang, Po-Jung Ruei-Chi Gan, Richie Chiu, Cheng-Hsun Tang, Petrus Molecular Regulation and Bioinformatics Laboratory Chang Gung University Taoyuan 333 Taiwan Division of Microbiology Graduate Institute of Biomedical Sciences Chang Gung University Taoyuan 333 Taiwan Institute of Biomedical Informatics National Yang-Ming University Taipei 112 Taiwan Taiwan International Graduate Program in Bioinformatics Academia Sinica Taipei 115 Taiwan Institute of Biomedical Sciences Academia Sinica Taipei 115 Taiwan Department of Parasitology National Cheng Kung University Tainan 701 Taiwan Key Laboratory of Genome Sciences and Information Beijing Institute of Genomics Chinese Academy of Sciences Beijing China Graduate University Chinese Academy of Sciences Beijing China Department of Life Sciences Chang Gung University Taoyuan 333 Taiwan Molecular Medicine Research Center Chang Gung University Taoyuan 333 Taiwan Bioinformatics Center Chang Gung University Tao-Yuan 333 Taiwan Chang Gung Molecular Infectious Diseases Research Center Chang Gung Memorial Hospital Taoyuan 333 Taiwan

MicroRNAs (miRNAs) are a class of small noncoding RNAs that have important regulatory roles in multicellular organisms. However, miRNA has never been identified experimentally in protist. Direct cloning of 438 expressed miRNA tags by microRNA serial analysis of gene expression from the parasitic protist Trichomonas vaginalis identified nine candidate miRNAs. bioinformatics analysis of the corresponding genomic region revealed that these miRNA candidates contain a classical stem-loop-stem structure of pre-microRNAs. Analysis of the 20 nt long mature tva-miR-001 showed that it is an intergenic miRNA located at the scaffold DS113596. Tva-miR-001 was differentially expressed in the trophozoite, pseudocyst and amoeboid stages. Based on the experimental results of the present study, we provided solid evidence that protist possesses a miRNA regulating network comparable with multicellular organisms for the first time. © 2009 Elsevier Inc. All rights reserved.

关键词： MicroRNA Protist Trichomonas vaginalis

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Global epidemiology and antimicrobial resistance of Enterobacterales harbouring genes encoding OXA-48-like carbapenemases: insights from the results of the Antimicrobial Testing Leadership and Surveillance (ATLAS) programme 2018-2021

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The Journal of antimicrobial chemotherapy 2024年第7期79卷 1581-1589页

作者： Yu-Lin Lee Wei-Yao Wang Wen-Chien Ko Po-Ren Hsueh Division of Infectious Disease Department of Internal Medicine Chung Shan Medical University Hospital Taichung Taiwan. PhD Program in Medical Biotechnology Institute of Genomics and Bioinformatics National Chung-Hsing University Taichung Taiwan. School of Medicine Chung Shan Medical University Taichung Taiwan. Department of Medicine College of Medicine National Cheng Kung University Tainan Taiwan. Departments of Laboratory Medicine and Internal Medicine China Medical University Hospital Chin Medical University Taichung Taiwan. School of Medicine China Medical University Taichung Taiwan. PhD Program for Ageing School of Medicine China Medical University Taichung Taiwan. Departments of Laboratory Medicine and Internal Medicine National Taiwan University Hospital National Taiwan University College of Medicine Taipei Taiwan.

OBJECTIVES:The recent emergence of carbapenem-resistant Enterobacterales poses a major and escalating threat to global public health. This study aimed to analyse the global distribution and antimicrobial resistance of Enterobacterales harbouring variant OXA-48-like carbapenemase-related genes. METHODS:Enterobacterales isolates were collected from the Antimicrobial Testing Leadership and Surveillance (ATLAS) programme during 2018-2021. Comprehensive antimicrobial susceptibility testing and β-lactamase gene detection were also conducted, along with statistical analysis of the collected data. RESULTS:Among the 72 244 isolates, 1934 Enterobacterales isolates were identified to harbour blaOXA-48-like genes, predominantly Klebsiella spp. (86.9%). High rates of multidrug resistance were observed, with only ceftazidime/avibactam and tigecycline showing favourable susceptibility. A discrepancy between the genotype and phenotype of carbapenem resistance was evident: 16.8% (233 out of 1384) of the Enterobacterales isolates with blaOXA-48-like genes exhibited susceptibility to meropenem. Specifically, 37.4% (64/95) of Escherichia coli strains with blaOXA-48-like genes displayed meropenem susceptibility, while the corresponding percentages for Klebsiella pneumoniae and Enterobacter cloacae complex were 25.2% (160/1184) and 0% (0/36), respectively (P < 0.05). Geographical analysis revealed that the highest prevalence of blaOXA-48-like genes occurred in Asia, the Middle East and Eastern Europe. The proportion of K. pneumoniae isolates harbouring blaOXA-232 increased from 23.9% in 2018 to 56.0% in 2021. By contrast, the proportion of blaOXA-48 decreased among K. pneumoniae isolates during 2018-2021. CONCLUSIONS:This study underscores the widespread and increasing prevalence of blaOXA-48-like genes in Enterobacterales and emphasizes the need for enhanced surveillance, improved diagnostic methods and tailored antibiotic stewardship to combat the spread of these resistant pathogens.

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Novel strategy for disease risk prediction incorporating predicted gene expression and DNA methylation data:a multi-phased study of prostate cancer

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Cancer Communications 2021年第12期41卷 1387-1397页

作者： Chong Wu Jingjing Zhu Austin King Xiaoran Tong Qing Lu Jong Y.Park Liang Wang Guimin Gao Hong-Wen Deng Yaohua Yang Karen E.Knudsen Timothy R.Rebbeck Jirong Long Wei Zheng Wei Pan David V.Conti Christopher A Haiman Lang Wu Department of Statistics Florida State UniversityTallahasseeFL 32304USA Cancer Epidemiology Division Population Sciences in the Pacific ProgramUniversity of Hawaii Cancer CenterUniversity of Hawaii at ManoaHonoluluHI 96813USA Department of Epidemiology and Biostatistics Michigan State UniversityEast LansingMI 48824USA Department of Biostatistics University of FloridaGainesvilleFL 32603USA Department of Cancer Epidemiology H.Lee Moffitt Cancer Center and Research InstituteTampaFL 33612USA Department of Tumor Biology H.Lee Moffitt Cancer Center and Research InstituteTampaFL 33612USA Department of Public Health Sciences University of ChicagoChicagoIL 60637USA Center of Bioinformatics and Genomics Department of Global Biostatistics and Data ScienceTulane UniversityNew OrleansLA 70112USA Division of Epidemiology Department of MedicineVanderbilt Epidemiology CenterVanderbilt-Ingram Cancer CenterVanderbilt University Medical CenterNashvilleTN 37203USA Department of Cancer Biology Sidney Kimmel Cancer CenterThomas Jefferson UniversityPhiladelphiaPA 19107USA Department of Medical Oncology Dana-Farber Cancer InstituteBostonMA 02215USA Department of Epidemiology Harvard TH Chan School of Public HealthBostonMA 02115USA Division of Biostatistics University of MinnesotaMinneapolisMN 55455USA Department of Preventive Medicine Keck School of MedicineUniversity of Southern California/Norris Comprehensive Cancer CenterLos AngelesCA 90033USA

Background:DNA methylation and gene expression are known to play important roles in the etiology of human diseases such as prostate cancer(PCa).However,it has not yet been possible to incorporate information of DNA methylation and gene expression into polygenic risk scores(PRSs).Here,we aimed to develop and validate an improved PRS for PCa risk by incorporating genetically predicted gene expression and DNA methylation,and other genomic information using an integrative ***:Using data from the PRACTICAL consortium,we derived multiple sets of genetic scores,including those based on available single-nucleotide polymorphisms through widely used methods of pruning and thresholding,LDpred,LDpred-funt,AnnoPred,and EBPRS,as well as PRS constructed using the genetically predicted gene expression and DNA methylation through a revised pruning and thresholding *** the tuning step,using the UK Biobank data(1458 prevalent cases and 1467 controls),we selected PRSs with the best *** an independent set of data from the UK Biobank,we developed an integrative PRS combining information from individual ***,in the testing step,we tested the performance of the integrative PRS in another independent set of UK Biobank data of incident cases and ***:Our constructed PRS had improved performance(C statistics:76.1%)over PRSs constructed by individual benchmark methods(from 69.6%to 74.7%).Furthermore,our new PRS had much higher risk assessment power than family *** overall net reclassification improvement was 69.0%by adding PRS to the baseline model compared with 12.5%by adding family ***:We developed and validated a new PRS which may improve the utility in predicting the risk of developing *** innovative method can also be applied to other human diseases to improve risk prediction across multiple outcomes.

关键词： risk prediction polygenic risk scores predicted gene expression predicted DNA methylation integrative models prostate cancer

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Inhibition of ADAM9 promotes the selective degradation of KRAS and sensitizes pancreatic cancers to chemotherapy

Nature Cancer

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Nature Cancer 2024年第3期5卷 400-419页

作者： Huang, Yu-Kai Cheng, Wei-Chung Kuo, Ting-Ting Yang, Juan-Cheng Wu, Yang-Chang Wu, Heng-Hsiung Lo, Chia-Chien Hsieh, Chih-Ying Wong, Sze-Ching Lu, Chih-Hao Wu, Wan-Ling Liu, Shih-Jen Li, Yi-Chuan Lin, Ching-Chan Shen, Chia-Ning Hung, Mien-Chie Lin, Jaw-Town Yeh, Chun-Chieh Sher, Yuh-Pyng Graduate Institute of Biomedical Sciences China Medical University Taichung Taiwan Cancer Biology and Precision Therapeutics Center China Medical University Taichung Taiwan Ph.D. Program for Cancer Biology and Drug Discovery China Medical University and Academia Sinica Taichung Taiwan School of Chinese Medicine College of Chinese Medicine China Medical University Taichung Taiwan Graduate Institute of Integrated Medicine College of Chinese Medicine China Medical University Taichung Taiwan Department of Medical Laboratory Science and Biotechnology College of Medical and Health Science Asia University Taichung Taiwan Center for Molecular Medicine China Medical University Hospital Taichung Taiwan Institute of Bioinformatics and Systems Biology National Yang Ming Chiao Tung University Taipei Taiwan National Institute of Infectious Diseases and Vaccinology National Health Research Institutes Miaoli Taiwan Graduate Institute of Medicine College of Medicine Kaohsiung Medical University Kaohsiung Taiwan Department of Biological Science and Technology China Medical University Taichung Taiwan Division of Hematology and Oncology China Medical University Hospital Taichung Taiwan Genomics Research Center Academia Sinica Taipei Taiwan Division of Gastroenterology and Hepatology Department of Internal Medicine E-Da Hospital Kaohsiung Taiwan Department of Medicine School of Medicine China Medical University Taichung Taiwan Department of Surgery Organ Transplantation Center China Medical University Hospital Taichung Taiwan Institute of Biochemistry and Molecular Biology China Medical University Taichung Taiwan

Kirsten rat sarcoma virus (KRAS) signaling drives pancreatic ductal adenocarcinoma (PDAC) malignancy, which is an unmet clinical need. Here, we identify a disintegrin and metalloproteinase domain (ADAM)9 as a modulator of PDAC progression via stabilization of wild-type and mutant KRAS proteins. Mechanistically, ADAM9 loss increases the interaction of KRAS with plasminogen activator inhibitor 1 (PAI-1), which functions as a selective autophagy receptor in conjunction with light chain 3 (LC3), triggering lysosomal degradation of KRAS. Suppression of ADAM9 by a small-molecule inhibitor restricts disease progression in spontaneous models, and combination with gemcitabine elicits dramatic regression of patient-derived tumors. Our findings provide a promising strategy to target the KRAS signaling cascade and demonstrate a potential modality to enhance sensitivity to chemotherapy in PDAC. © The Author(s), under exclusive licence to Springer Nature America, Inc. 2024.

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