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Transcriptomic and Network Signatures of Cryptic Fusion CBFA2T3-GLIS2 in Pediatric AML Reveals Clinical Considerations and Implications

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BLOOD 2017年第Sup1期130卷 1193-1193页

作者： Smith, Jenny L. Ries, Rhonda E. Schuback, Heather Louise Brodersen, Lisa E. Loken, Michael R. Bolouri, Hamid Meshinchi, Soheil Clinical Research Division Fred Hutchinson Cancer Research Center Seattle WA Applied Bioinformatics and Genomics Program University of Oregon Eugene OR Department of Pediatrics University of Washington School of Medicine Seattle WA Hematologics Inc Seattle WA Human Biology Division Fred Hutchinson Cancer Research Center Seattle Children's Oncology Group Monrovia CA Department of Pediatrics University of Washington Seattle Clinical Research Division Fred Hutchinson Cancer Rsrch. Ctr. Seattle WA

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Multimodal learning with graphs

arXiv

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arXiv 2022年

作者： Ektefaie, Yasha Dasoulas, George Noori, Ayush Farhat, Maha Zitnik, Marinka Bioinformatics and Integrative Genomics Program Harvard Medical School BostonMA02115 United States Department of Biomedical Informatics Harvard University BostonMA02115 United States Harvard College CambridgeMA02138 United States Broad Institute of MIT and Harvard CambridgeMA02142 United States Harvard Data Science Initiative CambridgeMA02138 United States Division of Pulmonary and Critical Care Department of Medicine Massachusetts General Hospital BostonMA United States

Artificial intelligence for graphs has achieved remarkable success in modeling complex systems, ranging from dynamic networks in biology to interacting particle systems in physics. However, the increasingly heterogeneous graph datasets call for multimodal methods that can combine different inductive biases—the set of assumptions that algorithms use to make predictions for inputs they have not encountered during training. Learning on multimodal datasets presents fundamental challenges because the inductive biases can vary by data modality and graphs might not be explicitly given in the input. To address these challenges, multimodal graph AI methods combine different modalities while leveraging cross-modal dependencies using graphs. Diverse datasets are combined using graphs and fed into sophisticated multimodal architectures, specified as image-intensive, knowledge-grounded and language-intensive models. Using this categorization, we introduce a blueprint for multimodal graph learning, use it to study existing methods and provide guidelines to design new models. © 2022, CC BY.

关键词： Blueprints

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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页

作者： Haengdueng Jeong Sung-Hee Kim Jiseon Kim Donghun Jeon Chanyang Uhm Heeju Oh Kyungrae Cho In Ho Park Jooyeon Oh Jeong Jin Kim Sang-Ho Jeong Ji-Ho Park Jun Won Park Jun-Won Yun Jun-Young Seo Jeon-Soo Shin James R Goldenring Je Kyung Seong Ki Taek Nam Department of Biomedical Sciences Brain Korea 21 PLUS Project for Medical Science Yonsei University College of Medicine Seoul 03722 Korea Epithelial Biology Center and Department of Surgery Vanderbilt University School of Medicine 10435-G MRB IV 2213 Garland Avenue Nashville Tennessee 37232 USA. Department of Biomedical Sciences Brain Korea 21 PLUS Project for Medical Science Yonsei University College of Medicine Seoul 03722 Korea. 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. Gyeongsang National University College of Medicine Seoul 08826 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 08826 South Korea. Institute of Immunology and Immunological Diseases Yonsei University College of Medicine Seoul South Korea Korea Mouse Phenotyping Center Seoul National University Seoul 08826 South Korea Laboratory of Developmental Biology and Genomics Research Institute for Veterinary Science and BK 21 PLUS Program for Creative Veterinary Science Research College of Veterinary Medicine Seoul National University Seoul South Korea BIO-MAX Institute Seoul National University Seoul 08826 South Korea Interdisciplinary Program for Bioinformatics Seoul National University Seoul 08826 South Korea. Electronic address: snumouse@snu.ac.kr. Department of Biomedical Sciences Brain Korea 21 PLUS Project for Medical Science Yonsei University College of Medicine Seoul 03722 Korea. Electronic address: kitaek@yuhs.ac.

BACKGROUNDS & AIMS:Since the Omicron variant emerged as a major 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 pathological 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 two 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.

关键词： Chronic gastritis Helicobacter pylori post-acute COVID-19 syndrome virus and diseases

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Targeting DNA junction sites by bis-intercalators induces topological changes with potent antitumor effects

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Nucleic acids research 2024年第15期52卷 9303-9316页

作者： Shih-Chun Huang Chia-Wei Chen Roshan Satange Chang-Chih Hsieh Chih-Chun Chang Shun-Ching Wang Chi-Li Peng Tai-Lin Chen Ming-Hsi Chiang Yih-Chern Horng Ming-Hon Hou Doctoral Program in Medical Biotechnology National Chung Hsing University Taichung 402 Taiwan. Graduate Institute of Genomics and Bioinformatics National Chung Hsing University Taichung 402 Taiwan. Department of Chemistry National Changhua University of Education Changhua 50058 Taiwan. Institute of Chemistry Academia Sinica Taipei 11528 Taiwan. Graduate Institute of Biotechnology National Chung Hsing University Taichung 402 Taiwan. Post Baccalaureate Medicine School of Medicine National Chung Hsing University Taichung 402 Taiwan. Biotechnology Center National Chung Hsing University Taichung 402 Taiwan.

Targeting inter-duplex junctions in catenated DNA with bidirectional bis-intercalators is a potential strategy for enhancing anticancer effects. In this study, we used d(CGTATACG)2, which forms a tetraplex base-pair junction that resembles the DNA-DNA contact structure, as a model target for two alkyl-linked diaminoacridine bis-intercalators, DA4 and DA5. Cross-linking of the junction site by the bis-intercalators induced substantial structural changes in the DNA, transforming it from a B-form helical end-to-end junction to an over-wounded side-by-side inter-duplex conformation with A-DNA characteristics and curvature. These structural perturbations facilitated the angled intercalation of DA4 and DA5 with propeller geometry into two adjacent duplexes. The addition of a single carbon to the DA5 linker caused a bend that aligned its chromophores with CpG sites, enabling continuous stacking and specific water-mediated interactions at the inter-duplex contacts. Furthermore, we have shown that the different topological changes induced by DA4 and DA5 lead to the inhibition of topoisomerase 2 activities, which may account for their antitumor effects. Thus, this study lays the foundations for bis-intercalators targeting biologically relevant DNA-DNA contact structures for anticancer drug development.

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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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Targeting human mitochondrial NAD(P)+-dependent malic enzyme (ME2) impairs energy metabolism and redox state and exhibits antileukemic activity in acute myeloid leukemia

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Cellular Oncology 2023年第5期46卷 1301-1316页

作者： Chen, Kun-Chi Hsiao, I-Hsin Huang, Yu-Nan Chou, Yu-Tung Lin, Yi-Chun Hsieh, Ju-Yi Chang, Yung-Lung Wu, Kang-Hsi Liu, Guang-Yaw Hung, Hui-Chih Department of Life Sciences National Chung Hsing University Taichung Taiwan Ph.D. Program in Tissue Engineering and Regenerative Medicine National Chung Hsing University Taichung Taiwan Department of Biochemistry National Defense Medical Center Taipei Taiwan School of Medicine Chung Shan Medical University Taichung Taiwan Department Pediatrics Chung Shan Medical University Hospital Taichung Taiwan Institute of Medicine College of Medicine Chung Shan Medical University Taichung Taiwan Institute of Genomics and Bioinformatics National Chung Hsing University Taichung Taiwan EGG & Animal Biotechnology Center National Chung Hsing University Taichung Taiwan

Acute myeloid leukemia (AML) is a fast-growing and highly fatal blood cancer, and recent research has shown that targeting metabolism may be a promising therapeutic approach for treating AML. One promising target is the human mitochondrial NAD(P)+-dependent malic enzyme (ME2), which is involved in the production of pyruvate and NAD(P)H and the regulation of the NAD+/NADH redox balance. Inhibition of ME2 via silencing ME2 or utilizing its allosteric inhibitor disodium embonate (Na2EA) causes a decrease in pyruvate and NADH, leading to a decrease in producing ATP via cellular respiration and oxidative phosphorylation. ME2 inhibition also decreases NADPH levels, resulting in an increase in reactive oxygen species (ROS) and oxidative stress, which ultimately leads to cellular apoptosis. Additionally, ME2 inhibition reduces pyruvate metabolism and the biosynthetic pathway. ME2 silencing inhibits the growth of xenotransplanted human AML cells, and the allosteric ME2 inhibitor Na2EA demonstrates antileukemic activity against immune-deficient mice with disseminated AML. Both of these effects are a result of impaired energy metabolism in mitochondria. These findings suggest that the targeting ME2 may be an effective strategy for treating AML. Overall, ME2 plays an essential role in energy metabolism of AML cells, and its inhibition may offer a promising approach for AML treatment.

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Impaired T cell and neoantigen retention in time-serial analysis of metastatic non-small cell lung cancer in patients unresponsive to TIL cell therapy

Nature Cancer

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Nature Cancer 2025年 1-19页

作者： Wang, Chao Yu, Xiaoqing Teer, Jamie K. Yao, Jiqiang Du, Dongliang Liu, Xiaoxian Thompson, Zachary J. Wang, Min Hsuan Welsh, Eric A. Memon, Danish Chan, Timothy A. Makarov, Vladimir Anadon, Carmen M. Saeed, Lamees Boyle, Theresa A. Fang, Bin Koomen, John M. Cox, Cheryl Landin, Ana M. Yoder, Sean J. Kim, Sungjune Chen, Dung-Tsa Pilon-Thomas, Shari A. Conejo-Garcia, Jose R. Antonia, Scott J. Haura, Eric B. Creelan, Benjamin C. Department of Immunology H. Lee Moffitt Cancer Center & Research Institute Tampa FL United States Department of Biostatistics and Bioinformatics H. Lee Moffitt Cancer Center & Research Institute Tampa FL United States Cancer Research UK Cambridge Institute University of Cambridge Cambridge United Kingdom Center for Immunotherapy and Precision Immuno-oncology Cleveland Clinic Lerner Research Institute Cleveland OH United States Department of Integrative Immunobiology Duke School of Medicine Durham NC United States Duke Cancer Institute Duke University School of Medicine Durham NC United States Department of Anatomic Pathology H. Lee Moffitt Cancer Center & Research Institute Tampa FL United States Proteomics & Metabolomics Core Facility H. Lee Moffitt Cancer Center & Research Institute Tampa FL United States Molecular Oncology H. Lee Moffitt Cancer Center & Research Institute Tampa FL United States Immune and Cellular Therapy Program H. Lee Moffitt Cancer Center & Research Institute Tampa FL United States Molecular Genomics Core Facility H. Lee Moffitt Cancer Center & Research Institute Tampa FL United States Department of Radiation Oncology Immunology Cancer Biology Mayo Clinic Alix College of Medicine & Health Sciences Jacksonville FL United States Department of Thoracic Oncology H. Lee Moffitt Cancer Center & Research Institute Tampa FL United States

Cell therapy with tumor-infiltrating lymphocytes (TILs) has yielded durable responses for multiple cancer types, but the causes of therapeutic resistance remain largely unknown. Here multidimensional analysis was performed on time-serial tumor and blood in a lung cancer TIL therapy trial. Using T cell receptor sequencing on both functionally expanded T cells and neoantigen-loaded tetramer-sorted T cells, we identified tumor antigen-specific T cell receptors. We then mapped clones into individual transcriptomes and found that tumor-reactive clonotypes expressed a dysfunctional program and lacked stem-like features among patients who lacked clinical benefit. Tracking tumor-reactive clonotypes over time, decay of antigen-reactive peripheral T cell clonotypes was associated with the emergence of progressive disease. Further, subclonal neoantigens previously targeted by infused T cells were subsequently absent within tumors at progression, suggesting potential adaptive resistance. Our findings suggest that targeting clonal antigens and circumventing dysfunctional states may be important for conferring clinical responses to TIL therapy. © The Author(s), under exclusive licence to Springer Nature America, Inc. 2025.

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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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S0103 Recurrent chimeric transcripts in human and mouse

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Journal of Animal Science 2016年第SUPPL_4期94卷 3-3页

作者： Djebali, S. Martín, B. Rodríguez Palumbo, E. Pervouchine, D. D. Breschi, A. Davis, C. Dobin, A. Alonso, G. Rastrojo, A. Aguado, B. Gingeras, T. R. Guigó, R. GenPhySE INRA Castanet-Tolosan France Universitat Pompeu Fabra (UPF) Barcelona Spain Bioinformatics and Genomics Program Centre for Genomic Regulation (CRG) Barcelona Spain Cold Spring Harbor Laboratory Functional Genomics Cold Spring Harbor NY Centro de Biología Molecular Severo Ochoa (CSIC- UAM) Madrid Spain

The formation of chimeric transcripts (chimeras) has been widely reported [1,2,3]. Some of them reflect underlying chromosomal rearrangements [4] or are the results of the propensity of reverse transcriptase to engage in template switching [5]. However, a proportion of cases genuinely appear to correspond to trans-splicing of RNAs, as has previously been described [6,7]. Here, we use ENCODE and mouse ENCODE deeply sequenced and bio-replicated RNaseq data from 18 human and 30 mouse samples, and the ChimPipe program to identify chimeras occurring in multiple biological samples (recurrent) and between the same pairs of genes in human and mouse, since they are more likely to be transcriptionally induced and functional. Recurrent common chimeras tend to connect gene pairs located on the same chromosome and relatively near each other (<100 kb), therefore pointing to polymerase read-through. However, interchromosomal chimeras are also observed, pointing to trans-splicing. Importantly, these recurrent chimeras tend to maintain an open reading frame and could therefore generate chimeric proteins. We also observed that not only the gene-to-gene connection is conserved, but strikingly so are specific junction sites. The genes connected in common chimeras tend to be involved in morphogenesis and body plan formation, and consistently tend to be detected in cell lines of embryonic origin. Validation of human chimeras by RT-PCR yielded a success rate of 50% and subsequent cloning and sequencing revealed novel transcript structures, of which some preserve the domains from the 2 parents’ genes. Applying this method to multiple animal species and breeds will help us understand chimera evolution, as well as reveal some links between genotype and phenotype.[1] Gingeras, T.R. Implications of chimeric non-co-linear transcripts. Nature, 2009[2] Kaessmann, H. Origins, evolution, and phenotypic impact of new genes. Genome Re, 2010[3] Djebali, S. et al. Evidence for transcript networks compo

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OP0149 CD4+ T CELLS FROM CHILDREN WITH ACTIVE JUVENILE IDIOPATHIC ARTHRITIS SHOW ABERRANT CHROMATIN ORGANIZATION AND CTCF LOCALIZATION ASSOCIATED WITH TRANSCRIPTIONAL ABNORMALITIES

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Annals of the Rheumatic Diseases 2019年 78卷 150-150页

作者： Evan Tarbell Kaiyu Jiang Teresa R. Hennon Lucy Holmes Patrick M. Gaffney Tao Liu Jim Jarvis University at Buffalo Biochemistry Buffalo United States of America University at Buffalo Pediatrics Buffalo United States of America Oklahoma Medical Research Foundation Arthritis and Immunology Program Oklahoma City United States of America University at Buffalo Genetics Genomics and Bioinformatics Program Buffalo United States of America

Background Our group and others have shown that peripheral blood cells of children with juvenile idiopathic arthritis (JIA) display numerous transcriptional abnormalities. However, most of these studies have been performed on mixed cell types (peripheral blood mononuclear cells, whole blood). Little cell type specific data is available, making mechanistic inferences and links to disease pathogenesis difficult. Objectives To define transcriptional patterns in CD4+ T cells from children with polyarticular JIA and query mechanisms underlying transcriptional abnormalities. Methods We studied CD4+ T cells obtained from children with active polyarticular onset JIA and sought to identify epigenetic features associated with altered gene expression. We performed RNA-seq and ATAC-seq on a cohort of patients who had the active disease and were under treatment with methotrexate and etanercept (ADT), patients who fit criteria for clinical remission on medication (CRM), and healthy control children (HC). We used standard used the common dispersion protocol in EdgeR to identify differential gene expression. We used our recently developed and validated Hidden Markov ModeleR for ATAC-seq doftware to identify differentially accessible regions, comparing ADT, CRM, and HC samples. We integrated ATACseq and RNAseq data using the BETA software package. After preliminary analysis revealed a potential role for the transcriptional regulator, CCCTC binding factor (CTCF) in the observed transcriptional patterns, we performed ChIPseq and HiChIP studies on an independent group of JIA CD4+ T cell samples. Results We found widespread transcriptomic differences between ADT and either HC or CRM patients. We identified 4,062 genes that showed differential expression between ADT and HC samples. Gene expression patterns from CRM samples were nearly identical to healthy controls, suggesting that remission largely results in normalization of CD4+ T cell transcriptomes. We performed transcription factor

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