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Cell Reports medicine 2025年第5期6卷 102084-102084页

作者： Han, Xudong Zhang, Yichi Petrosky, Jillian N. Bald, Sarah Sherva, Richard M. Labadorf, Adam Cherry, Jonathan D. Chung, Jaeyoon Farrell, Kurt Abdolmohammadi, Bobak Durape, Shruti Martin, Brett M. Palmisano, Joseph N. Farrell, John J. Alvarez, Victor E. Huber, Bertrand R. Dwyer, Brigid Daneshvar, Daniel H. Jun, Gyungah R. Lunetta, Kathryn L. Goldstein, Lee E. Katz, Douglas I. Cantu, Robert C. Shenton, Martha E. Cummings, Jeffrey L. Reiman, Eric M. Stern, Robert A. Alosco, Michael L. Tripodis, Yorghos Farrer, Lindsay A. Stein, Thor D. Crary, John F. McKee, Ann C. Mez, Jesse Bioinformatics Graduate Program Boston University Boston MA United States Section of Biomedical Genetics Department of Medicine Boston University Chobanian & Avedisian School of Medicine Boston MA United States Department of Neurology Boston University Chobanian & Avedisian School of Medicine Boston MA United States Boston University Alzheimer's Disease Research Center Boston University Chobanian & Avedisian School of Medicine Boston MA United States Boston VA Healthcare System Boston MA United States Boston University Chronic Traumatic Encephalopathy Center Boston University Boston MA United States Department of Pathology and Laboratory Medicine Boston University Chobanian & Avedisian School of Medicine Boston MA United States Departments of Pathology Neuroscience and Artificial Intelligence & Human Health Neuropathology Brain Bank & Research CoRE Friedman Brain Institute Ronald M. Loeb Center for Alzheimer's Disease Icahn School of Medicine at Mount Sinai New York NY United States Biostatistics and Epidemiology Data Analytics Center Boston University School of Public Health Boston MA United States Bedford VA Healthcare System Bedford MA United States Braintree Rehabilitation Hospital Braintree MA United States Department of Physical Medicine and Rehabilitation Harvard Medical School Boston MA United States Department of Rehabilitation and Human Performance Brain Injury Research Center Icahn School of Medicine at Mount Sinai New York NY United States Department of Neurology Icahn School of Medicine at Mount Sinai New York NY United States Department of Biostatistics Boston University School of Public Health Boston MA United States Department of Ophthalmology Boston University Chobanian & Avedisian School of Medicine Boston MA United States Departments of Biomedical Electrical & Computer Engineering Boston University College of Engineering Boston MA United States Departments of Radiology and Psychiatry Boston University Chobanian & Avedisia

Chronic traumatic encephalopathy (CTE) is a neurodegenerative tauopathy associated with repetitive head impact (RHI) exposure. Genetic variation in the 17q21.31 region, containing microtubule-associated protein tau (MAPT), has been implicated in tauopathies but has not been investigated in CTE. The region includes a megabase-long inversion (H1/H2) and copy-number variations, including α, β, and γ segments, which can be characterized as nine segregating structural haplotypes. We leveraged array SNP data and a reference panel across the 17q21.31 region to impute structural haplotypes and test their association with CTE endophenotypes in 447 European ancestry brain donors with RHI exposure. The H1β1γ1 haplotype was significantly associated with dementia and semi-quantitative tau burden in multiple cortical and medial temporal regions commonly affected in CTE. H1β1γ1 differential expression analyses in dorsolateral frontal cortex implicated cis-acting genes and inflammatory pathways. Taken together, the H1β1γ1 haplotype may help explain CTE heterogeneity among those with similar RHI exposure. © 2025 The Authors

关键词： 17q21.31 chronic traumatic encephalopathy dementia differential gene expression immune system MAPT repetitive head impacts structural haplotypes tauopathy traumatic brain injury

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A novel framework for human leukocyte antigen (HLA) genotyping using probe capture-based targeted next-generation sequencing and computational analysis

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Computational and Structural Biotechnology Journal 2024年 23卷 1562-1571页

作者： Lai, Sheng-Kai Luo, Allen Chilun Chiu, I-Hsuan Chuang, Hui-Wen Chou, Ting-Hsuan Hung, Tsung-Kai Hsu, Jacob Shujui Chen, Chien-Yu Yang, Wei-Shiung Yang, Ya-Chien Chen, Pei-Lung Genome and Systems Biology Degree Program Academia Sinica and National Taiwan University Taipei Taiwan Department of Medical Genetics National Taiwan University Hospital Taipei Taiwan Graduate Institute of Medical Genomics and Proteomics College of Medicine National Taiwan University Taipei Taiwan Department of Biomechatronics Engineering National Taiwan University Taipei Taiwan Graduate Institute of Clinical Medicine College of Medicine National Taiwan University Taipei Taiwan Division of Endocrinology and Metabolism Department of Internal Medicine National Taiwan University Hospital Taipei Taiwan Department of Clinical Laboratory Sciences and Medical Biotechnology College of Medicine National Taiwan University Taipei Taiwan Department of Laboratory Medicine National Taiwan University Hospital Taipei Taiwan

Human leukocyte antigen (HLA) genes play pivotal roles in numerous immunological applications. Given the immense number of polymorphisms, achieving accurate high-throughput HLA typing remains challenging. This study aimed to harness the human pan-genome reference consortium (HPRC) resources as a potential benchmark for HLA reference materials. We meticulously annotated specific four field-resolution alleles for 11 HLA genes (HLA-A, -B, -C, -DPA1, -DPB1, -DQA1, -DQB1, -DRB1, -DRB3, -DRB4 and -DRB5) from 44 high-quality HPRC personal genome assemblies. For sequencing, we crafted HLA-specific probes and conducted capture-based targeted sequencing of the genomic DNA of the HPRC cohort, ensuring focused and comprehensive coverage of the HLA region of interest. We used publicly available short-read whole-genome sequencing (WGS) data from identical samples to offer a comparative perspective. To decipher the vast amount of sequencing data, we employed seven distinct software tools: OptiType, HLA-VBseq, HISAT genotype, SpecHLA, T1K, QzType, and DRAGEN. Each tool offers unique capabilities and algorithms for HLA genotyping, allowing comprehensive analysis and validation of the results. We then compared these results with benchmarks derived from personal genome assemblies. Our findings present a comprehensive four-field-resolution HLA allele annotation for 44 HPRC samples. Significantly, our innovative targeted next-generation sequencing (NGS) approach for HLA genes showed superior accuracy compared with conventional short-read WGS. An integrated analysis involving QzType, T1K, and DRAGEN was developed, achieving 100% accuracy for all 11 HLA genes. In conclusion, our study highlighted the combination of targeted short-read sequencing and astute computational analysis as a robust approach for HLA genotyping. Furthermore, the HPRC cohort has emerged as a valuable assembly-based reference in this realm. © 2024 The Authors

关键词： Probes

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Lessons learned: establishing a CLIA-equivalent laboratory for targeted mass spectrometry assays – navigating the transition from research to clinical practice

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Clinical proteomics 2024年第1期21卷 1-11页

作者： Han, Chia-Li Lai, Chi-Ting Reyes, Aaron James Yang, Hao-Chin Lu, Jin-Ying Shih, Shyang-Rong Chen, Kuen-Yuan Hoofnagle, Andrew N. Yu, Sung-Liang Bocik, William Hiltke, Tara Chiu, Huan-Chi Wan, Ching-Yi Rodriguez, Henry Zhang, Victoria Chen, Yu-Ju Master Program in Clinical Genomics and Proteomics College of Pharmacy Taipei Medical University Taipei Taiwan Institute of Chemistry Academia Sinica Taipei Taiwan Division of Endocrinology and Metabolism Department of Internal Medicine National Taiwan University Hospital Taipei Taiwan Department of Surgery National Taiwan University Hospital Taipei Taiwan Department of Laboratory Medicine and Pathology University of Washington Seattle WA United States Department of Clinical Laboratory Sciences and Medical Biotechnology National Taiwan University College of Medicine Taipei Taiwan Centers for Genomics and Precision Medicine National Taiwan University Taipei Taiwan Cancer Research Technology Program Proteome Characterization Laboratory Frederick National Laboratory for Cancer Research Frederick MD United States Office of Cancer Clinical Proteomics Research National Cancer Institute Rockville MD United States Department of Pathology and Laboratory Medicine University of Rochester Medical Center Rochester NY United States Department of Chemistry National Taiwan University Taipei Taiwan

Mass spectrometry (MS) assays offer exceptional capabilities in high multiplexity, specificity, and throughput. As proteomics technologies continue advancements to identify new disease biomarkers, transition of these innovations from research settings to clinical applications becomes imperative. To meet the rigorous regulatory standards of clinical laboratories, development of a clinical protein MS assay necessitates adherence to stringent criteria. To illustrate the process, this project focused on using thyroglobulin (Tg) as a biomarker and an immuno-multiple reaction monitoring (iMRM) MS-based assay as a model for establishing a Clinical Laboratory Improvement Amendments (CLIA) compliant laboratory within the Centers of Genomic and Precision medicine, National Taiwan University. The chosen example also illustrates the clinical utility of MS assays to complement conventional immunoassay-based methods, particularly in cases where the presence of autoantibodies in 10–30% of patients hinders accuracy. The laboratory design entails a comprehensive coordination in spatial layout, workflow organization, equipment selection, ventilation systems, plumbing, electrical infrastructure, documentation procedures, and communication protocols. Practical aspects of the transformation process, including preparing laboratory facilities, testing environments, instrument validation, assay development and validation, quality management, sample testing, and personnel competency, are discussed. Finally, concordant results in proficiency testing demonstrate the harmonization with the University of Washington Medical Center and the quality assurance of the CLIA-equivalent Tg-iMRM MS assay established in Taiwan. The realization of this model protein MS assay in Taiwan highlights the feasibility of international joint development and provides a detailed reference map to expedite the implementation of more MS-based protein assays in clinical laboratories for patient care. © The Author(s) 202

关键词： Clinical laboratory improvement amendments (CLIA) Immuno-multiple reaction monitoring (iMRM) mass spectrometry Targeted mass spectrometry Thyroglobulin assay

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Identify Non-mutational p53 Functional Deficiency in Human Cancers

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genomics, proteomics & bioinformatics 2024年第5期22卷 85-98页

作者： Qianpeng Li Yang Zhang Sicheng Luo Zhang Zhang Ann L.Oberg David E.Kozono Hua Lu Jann N.Sarkaria Lina Ma Liguo Wang National Genomics Data Center China National Center for BioinformationBeijing 100101China Beijing Institute of Genomics Chinese Academy of SciencesBeijing 100101China University of Chinese Academy of Sciences Beijing 100049China Division of Computational Biology Mayo Clinic College of Medicine and ScienceRochesterMN 55905USA Department of Radiation Oncology Dana-Farber Cancer Institute and Brigham and Women's HospitalBostonMA 02215USA Department of Biochemistry&Molecular Biology and Tulane Cancer Center Tulane University School of MedicineNew OrleansLA 70112USA Department of Radiation Oncology Mayo Clinic College of Medicine and ScienceRochesterMN 55905USA Department of Biochemistry and Molecular Biology Mayo Clinic College of Medicine and ScienceRochesterMN 55905USA Bioinformatics and Computational Biology Graduate Program University of Minnesota RochesterRochesterMN 55904USA

An accurate assessment of p53's functional statuses is critical for cancer genomic ***,there is a significant challenge in identifying tumors with non-mutational p53 inactivation which is not detectable through DNA *** undetected cases are often misclassified as p53-normal,leading to inaccurate prognosis and downstream association *** address this issue,we built the support vector machine(SVM)models to systematically reassess p53's functional statuses in TP53 wild-type(TP53^(WT))tumors from multiple The Cancer Genome Atlas(TCGA)***-validation demonstrated the good performance of the SVM models with a mean area under the receiver operating characteristic curve(AUROC)of 0.9822,precision of 0.9747,and recall of *** study revealed that a significant proportion(87%-99%)of TP53^(WT) tumors actually had compromised p53 *** analyses uncovered that these genetically intact but functionally impaired(termed as predictively reduced function of p53 or TP53^(WT)-pRF)tumors exhibited genomic and pathophysiologic features akin to TP53-mutant tumors:heightened genomic instability and elevated levels of ***,patients with TP53^(WT)-pRF tumors experienced significantly shortened overall survival or progression-free survival compared to those with predictively normal function of p53(TP53^(WT)-pN)tumors,and these patients also displayed increased sensitivity to platinum-based chemotherapy and radiation therapy.

关键词： Cancer Composite expression DNA mutation Machine learning p53 deficiency

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Gut mucosal microbiota profiles linked to colorectal cancer recurrence

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World Journal of Gastroenterology 2022年第18期28卷 1946-1964页

作者： Rui-Xue Huo Yi-Jia Wang Shao-Bin Hou Wei Wang Chun-Ze Zhang Xue-Hua Wan Department of Oncology Tianjin Union Medical CenterNankai UniversityTianjin 300121China Laboratory of Oncologic Molecular Medicine Tianjin Union Medical CenterNankai UniversityTianjin 300121China Advanced Studies in Genomics Proteomics and BioinformaticsUniversity of Hawaii at ManoaHonoluluHI 96822United States TEDA Institute of Biological Sciences and Biotechnology Nankai UniversityTianjin 300457China Department of Colorectal Surgery Tianjin Union Medical CenterNankai UniversityTianjin 300121China Tianjin Institute of Coloproctology Tianjin 300121China

BACKGROUND Emerging evidence links gut microbiota to various human diseases including colorectal cancer(CRC)initiation and ***,gut microbiota profiles associated with CRC recurrence and patient prognosis are not completely understood yet,especially in a Chinese *** To investigate the relationship between gut mucosal microbiota profiles and CRC recurrence and patient *** We obtained the composition and structure of gut microbiota collected from 75 patients diagnosed with CRC and 26 healthy *** patients were followed up by regular examination to determine whether tumors ***-paired samples from on-tumor,adjacent-tumor and off-tumor sites of patients diagnosed with/without CRC recurrence were analyzed to assess spatial-specific patterns of gut mucosal microbiota by 16S ribosomal RNA ***,we carried out bioinformatic analyses,Kaplan-Meier survival analyses and Cox regression analyses to determine the relationship between gut mucosal microbiota profiles and CRC recurrence and patient *** We observed spatial-specific patterns of gut mucosal microbiota profiles linked to CRC recurrence and patient prognosis.A total of 17 bacterial genera/families were identified as potential biomarkers for CRC recurrence and patient prognosis,including Anaerotruncus,Bacteroidales,Coriobacteriaceae,Dialister,Eubacterium,Fusobacterium,Filifactor,Gemella,Haemophilus,Mogibacteriazeae,Pyramidobacter,Parvimonas,Porphyromonadaceae,Slackia,Schwartzia,TG5 and *** Our work suggests that intestinal microbiota can serve as biomarkers to predict the risk of CRC recurrence and patient death.

关键词： Gut microbiota Colorectal cancer Prognosis Colorectal cancer recurrence Biomarker 16S rRNA sequencing analysis

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Proteome-Wide Analysis Using SOMAscan Identifies and Validates Epidermal Growth Factor as a Disease Marker of Collagenous Gastritis

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Gastro Hep Advances 2022年第5期1卷 689-702页

作者： Curci, Debora Dillon, Simon T. Gu, Xuesong Winter, Harland Libermann, Towia A. Institute for Maternal and Child Health - IRCCS “Burlo Garofolo” Advanced Diagnostic and Translational Medicine Laboratory Trieste Italy Division of Interdisciplinary Medicine and Biotechnology Beth Israel Deaconess Medical Center Boston MA United States Beth Israel Deaconess Medical Center Genomics Proteomics Bioinformatics and Systems Biology Center Boston MA United States Department of Medicine Harvard Medical School Boston MA United States Center for Pediatric Inflammatory Bowel Disease Massachusetts General Hospital Boston MA United States

Background and Aims: Collagenous gastritis (CG) is a rare disorder characterized by increased subepithelial collagen deposition and inflammatory infiltrates. The mechanisms involved in CG pathogenesis are poorly understood, and no CG-associated biomarkers have been identified. This proteomics study identified serum biomarkers and pathogenic pathways to provide new knowledge about the pathobiology of CG, a disease reported in less than 100 patients. Methods: Nine serum samples from pediatric patients diagnosed with CG were evaluated using novel aptamer-based proteomic technology and systems biology to generate new knowledge about the complex interactions between the differentially expressed proteins and candidate upstream regulators, using the Ingenuity Pathway Analysis in patients with non-CG and patients with normal gastric biopsies or nongastritis (NG). Results: SOMAscan analysis identified 63 proteins significantly dysregulated in CG as compared to non-CG or NG patients that converged around enhanced inflammatory response and immune cell migration but reduced vascular functions. Principal component analysis using 15 of those proteins accurately separated the CG cases from the 2 comparator control groups. Using immunoassays, serum epidermal growth factor concentrations in CG patients, a protein involved in collagen production, were confirmed to be significantly lower than those in gastritis/NG patients. Conclusion: This is the first comprehensive analysis of the proteome in CG patients that reveals metabolic pathways relating inflammation and fibrosis as well as a new potential role of epidermal growth factor as a disease biomarker. © 2022 The Authors

关键词： Biomarker Collagenous Gastritis Epidermal Growth Factor proteomics

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Post-COVID-19 Effects on Chronic Gastritis and Gastric Cellular and Molecular Characteristics in Male Mice

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Cellular and Molecular Gastroenterology and Hepatology 2025年第8期19卷 101511-101511页

作者： Jeong, Haengdueng Kim, Sung-Hee Kim, Jiseon Jeon, Donghun Uhm, Chanyang Oh, Heeju Cho, Kyungrae Park, In Ho Oh, Jooyeon Kim, Jeong Jin Jeong, Sang-Ho Park, Ji-Ho Park, Jun Won Yun, Jun-Won Seo, Jun-Young Shin, Jeon-Soo Goldenring, James R. Seong, Je Kyung Nam, Ki Taek Department of Biomedical Sciences Brain Korea 21 PLUS Project for Medical Science Yonsei University College of Medicine Seoul South Korea Epithelial Biology Center and Department of Surgery Vanderbilt University School of Medicine Nashville TN United States Institute of Immunology and Immunological Diseases Yonsei University College of Medicine Seoul South Korea Department of Microbiology Yonsei University College of Medicine Seoul South Korea Department of Surgery Gyongsang National University Hospital Jinju South Korea Korea Mouse Phenotyping Center Seoul National University Seoul South Korea Laboratory of Developmental Biology and Genomics Research Institute for Veterinary Science Brain Korea 21 PLUS Program for Creative Veterinary Science Research College of Veterinary Medicine Seoul National University Seoul South Korea Laboratory Animal Medicine College of Veterinary Medicine Seoul National University Seoul South Korea Laboratory of Veterinary Toxicology College of Veterinary Medicine Seoul National University Seoul South Korea BIO-MAX Institute Seoul National University Seoul South Korea Interdisciplinary Program for Bioinformatics Seoul National University Seoul South Korea

Backgrounds & Aims: Since the Omicron variant emerged as a major severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variant, COVID-19-associated mortality has decreased remarkably. Nevertheless, patients with a history of SARS-CoV-2 infection have been suffering from an aftereffect commonly known as ‘long COVID,’ affecting diverse organs. However, the effect of SARS-CoV-2 on gastric cells and disease progression was not previously known. We aimed to investigate whether SARS-CoV-2 infection affects stomach cells and if post-COVID-19 conditions can lead to severe gastric disease. Methods: Stomach specimens obtained from male K18-hACE2 mice 7 days after SARS-CoV-2 infection were subjected to a transcriptomic analysis for molecular profiling. To investigate the putative role of SARS-CoV-2 in gastric carcinogenesis, K18-hACE2 mice affected by nonlethal COVID-19 were also inoculated with Helicobacter pylori SS1. Results: Despite the lack of viral dissemination and pathologic traits in the stomach, SARS-CoV-2 infection caused dramatic changes to the molecular profile and some immune subsets in this organ. Notably, the gene sets related to metaplasia and gastric cancer were significantly enriched after viral infection. As a result, chronic inflammatory responses and preneoplastic transitions were promoted in these mice. Conclusion: SARS-CoV-2 infection indirectly leads to profound and post-acute COVID-19 alterations in the stomach at the cellular and molecular levels, resulting in adverse outcomes following co-infection with SARS-CoV-2 and H pylori. Our results show that 2 prevalent pathogens of humans elicit a negative synergistic effect and provide evidence of the risk of severe chronic gastritis in the post-COVID-19 era. © 2025 The Authors

关键词： Chronic Gastritis Helicobacter pylori Post-acute COVID-19 Syndrome Virus and Diseases

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The recency and geographical origins of the bat viruses ancestral to SARS-CoV and SARS-CoV-2

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Cell 2025年

作者： Pekar, Jonathan E. Lytras, Spyros Ghafari, Mahan Magee, Andrew F. Parker, Edyth Wang, Yu Ji, Xiang Havens, Jennifer L. Katzourakis, Aris Vasylyeva, Tetyana I. Suchard, Marc A. Hughes, Alice C. Hughes, Joseph Rambaut, Andrew Robertson, David L. Dellicour, Simon Worobey, Michael Wertheim, Joel O. Lemey, Philippe Institute of Ecology and Evolution University of Edinburgh Edinburgh United Kingdom Bioinformatics and Systems Biology Graduate Program University of California San Diego La Jolla 92093 CA United States Department of Biomedical Informatics University of California San Diego La Jolla 92093 CA United States Department of Medicine University of California San Diego La Jolla 92093 CA United States Division of Systems Virology Department of Microbiology and Immunology The Institute of Medical Science The University of Tokyo Tokyo Japan Medical Research Council University of Glasgow Centre for Virus Research Glasgow United Kingdom Department of Biology University of Oxford Oxford United Kingdom Department of Human Genetics David Geffen School of Medicine University of California Los Angeles Los Angeles 90095 CA United States Department of Immunology and Microbiology The Scripps Research Institute La Jolla 92037 CA United States Institute of Genomics and Global Health Redeemer's University Osun State Ede Nigeria Department of Computer Science and Engineering University of California San Diego La Jolla 92093 CA United States Department of Mathematics School of Science and Engineering Tulane University New Orleans LA United States Department of Population Health and Disease Prevention University of California Irvine Irvine 92617 CA United States Department of Biostatistics Fielding School of Public Health University of California Los Angeles Los Angeles 90095 CA United States Department of Computational Medicine David Geffen School of Medicine University of California Los Angeles Los Angeles 90095 CA United States School of Biological Sciences University of Hong Kong Hong Kong Hong Kong China Biodiversity Green Development Foundation Beijing China Spatial Epidemiology Lab (SpELL) Université Libre de Bruxelles CP160/12 50 av. FD Roosevelt Bruxelles 1050 Belgium Department of Microbiology Immunology and Transplantation Rega Institute

The emergence of SARS-CoV in 2002 and SARS-CoV-2 in 2019 led to increased sampling of sarbecoviruses circulating in horseshoe bats. Employing phylogenetic inference while accounting for recombination of bat sarbecoviruses, we find that the closest-inferred bat virus ancestors of SARS-CoV and SARS-CoV-2 existed less than a decade prior to their emergence in humans. Phylogeographic analyses show bat sarbecoviruses traveled at rates approximating their horseshoe bat hosts and circulated in Asia for millennia. We find that the direct ancestors of SARS-CoV and SARS-CoV-2 are unlikely to have reached their respective sites of emergence via dispersal in the bat reservoir alone, supporting interactions with intermediate hosts through wildlife trade playing a role in zoonotic spillover. These results can guide future sampling efforts and demonstrate that viral genomic regions extremely closely related to SARS-CoV and SARS-CoV-2 were circulating in horseshoe bats, confirming their importance as the reservoir species for SARS viruses. © 2025 The Authors

关键词： molecular epidemiology phylogeography sarbecoviruses virus evolution

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In vitro activity of imipenem/relebactam, meropenem/vaborbactam and comparators against Enterobacterales from patients with intra-abdominal infections: Results of the study for Monitoring Antimicrobial Resistance Trends (SMART) in Taiwan, 2020

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Journal of Microbiology, Immunology and Infection 2023年第1期56卷 75-83页

作者： Lee, Yu-Lin Ko, Wen-Chien Hsueh, Po-Ren Department of Internal Medicine Changhua Christian Hospital Changhua Taiwan Institute of Genomics and Bioinformatics National Chung Hsing University Taichung Taiwan Department of Internal Medicine Chung Shan Medical University Hospital 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 Taichung Taiwan School of Medicine China Medical University Taichung Taiwan Ph.D Program for Aging 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

Background: Multi-drug resistant Enterobacterales is a growing health threat. Imipenem/relebactam and meropenem/vaborbactam, are not clinically used in Taiwan and the susceptibility is lack from routine laboratory tests. Methods: Broth microdilution method was used to determine the minimum inhibitory concentrations (MICs) and interpreted according to the Clinical and Laboratory Standards Institute (CLSI) breakpoints criteria. Isolates that were not susceptible to imipenem (MIC ≥ 2 mg/L), imipenem/relebactam (MIC ≥ 2 mg/L), or ceftolozane-tazobactam (MIC ≥ 4 mg/L) were selected for further molecular testing for genes encoding extended-spectrum beta-lactamases (ESBLs), AmpC β-lactamases, and carbapenemases by multiplex PCR assays. Results: A total of 290 Enterobacterales isolates from 9 participating hospitals were collected in 2020. Escherichia coli (n = 135, 46.6%) and Klebsiella pneumoniae (n = 88, 30.3%) were two leading pathogens of all Enterobacterales isolates. The antimicrobial agents with susceptibility rates more than 90% included amikacin (99.3%, 288/290), ertapenem (90.0%, 261/290), meropenem (97.2%, 282/290), imipenem/relebactam (94.8%, 275/290) and meropenem/vaborbactam (99.3%, 288/290). K. pneumoniae isolates were less susceptible to ertapenem, imipenem, meropenem, piperacillin-tazobactam and ceftozolane/tazobactam than E. coli (all p < 0.05). ESBL, AmpC, and carbapenemase were detected in 40.5% (17/42), 45.2% (19/42) and 11.9% (5/42) among tested isolates, respectively. The 5 carbapenemase genes included 4 bla_KPC and 1 bla_IMP. The imipenem-non-susceptible isolates (n = 30) had higher susceptibility rates to meropenem/vaborbactam (93.3%, 28/30) than imipenem/relebactam (50%, 12/30) (p < 0.05). Conclusions: Imipenem/relebactam and meropenem/vaborbactam had excellent efficacy against Enterobacterales isolates. Meropenem/vaborbactam allowed better salvage therapy for carbapenem-resistant Enterobacterales infections. © 2022

关键词： Carbapenem resistance Cross resistance Enterobacterales Multidrug resistance (MDR) Novel β-lactam combination agents

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Phosphoproteomics of Klebsiella pneumoniae NTUH-K2044 reveals a tight link between tyrosine phosphorylation and virulence

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Molecular and Cellular proteomics 2009年第12期8卷 2613-2623页

作者： Lin, Miao-Hsia Hsu, Tung-Li Lin, Shu-Yu Pan, Yi-Jiun Jan, Jia-Tsrong Wang, Jin-Town Khoo, Kay-Hooi Wu, Shih-Hsiung Institute of Biochemical Sciences College of Life Sciences National Taiwan University Taipei 106 Taiwan Institute of Biological Chemistry Academia Sinica Taipei 115 Taiwan National Research Program for Genomic Medicine Core Facilities for Proteomics Research Academia Sinica Taipei 115 Taiwan Genomics Research Center Academia Sinica Taipei 115 Taiwan Department of Microbiology National Taiwan University College of Medicine Taipei 100 Taiwan

Encapsulated Klebsiella pneumoniae is the predominant causative agent of pyogenic liver abscess, an emerging infectious disease that often complicates metastatic meningitis or endophthalmitis. The capsular polysaccharide on K. pneumoniae surface was determined as the key to virulence. Although the regulation of capsular polysaccharide biosynthesis is largely unclear, it was found that protein-tyrosine kinases and phosphatases are involved. Therefore, the identification and characterization of such kinases, phosphatases, and their substrates would advance our knowledge of the underlying mechanism in capsule formation and could contribute to the development of new therapeutic strategies. Here, we analyzed the phosphoproteome of K. pneumoniae NTUH-K2044 with a shotgun approach and identified 117 unique phosphopeptides along with 93 in vivo phosphorylated sites corresponding to 81 proteins. Interestingly, three of the identified tyrosine phosphorylated proteins, namely protein-tyrosine kinase (Wzc), phosphomannomutase (ManB), and undecaprenyl-phosphate glycosyltransferase (WcaJ), were found to be distributed in the cps locus and thus were speculated to be involved in the converging signal transduction of capsule biosynthesis. Consequently, we decided to focus on the lesser studied ManB and WcaJ for mutation analysis. The capsular polysaccharides of WcaJ mutant (WcaJY5F) were dramatically reduced quantitatively, and the LD₅₀ increased by 200-fold in a mouse peritonitis model compared with the wild-type strain. However, the capsular polysaccharides of ManB mutant (ManBY26F) showed no difference in quantity, and the LD₅₀ increased by merely 6-fold in mice test. Our study provided a clear trend that WcaJ tyrosine phosphorylation can regulate the biosynthesis of capsular polysaccharides and result in the pathogenicity of K. pneumoniae NTUH-K2044. © 2009 by The American Society for Biochemistry and Molecular Biology, Inc.

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