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Genetic drivers of heterogeneity in type 2 diabetes pathophysiology

Nature 2024年第8003期627卷 347-357页

作者： Ken Suzuki Konstantinos Hatzikotoulas Lorraine Southam Henry J Taylor Xianyong Yin Kim M Lorenz Ravi Mandla Alicia Huerta-Chagoya Giorgio E M Melloni Stavroula Kanoni Nigel W Rayner Ozvan Bocher Ana Luiza Arruda Kyuto Sonehara Shinichi Namba Simon S K Lee Michael H Preuss Lauren E Petty Philip Schroeder Brett Vanderwerff Mart Kals Fiona Bragg Kuang Lin Xiuqing Guo Weihua Zhang Jie Yao Young Jin Kim Mariaelisa Graff Fumihiko Takeuchi Jana Nano Amel Lamri Masahiro Nakatochi Sanghoon Moon Robert A Scott James P Cook Jung-Jin Lee Ian Pan Daniel Taliun Esteban J Parra Jin-Fang Chai Lawrence F Bielak Yasuharu Tabara Yang Hai Gudmar Thorleifsson Niels Grarup Tamar Sofer Matthias Wuttke Chloé Sarnowski Christian Gieger Darryl Nousome Stella Trompet Soo-Heon Kwak Jirong Long Meng Sun Lin Tong Wei-Min Chen Suraj S Nongmaithem Raymond Noordam Victor J Y Lim Claudia H T Tam Yoonjung Yoonie Joo Chien-Hsiun Chen Laura M Raffield Bram Peter Prins Aude Nicolas Lisa R Yanek Guanjie Chen Jennifer A Brody Edmond Kabagambe Ping An Anny H Xiang Hyeok Sun Choi Brian E Cade Jingyi Tan K Alaine Broadaway Alice Williamson Zoha Kamali Jinrui Cui Manonanthini Thangam Linda S Adair Adebowale Adeyemo Carlos A Aguilar-Salinas Tarunveer S Ahluwalia Sonia S Anand Alain Bertoni Jette Bork-Jensen Ivan Brandslund Thomas A Buchanan Charles F Burant Adam S Butterworth Mickaël Canouil Juliana C N Chan Li-Ching Chang Miao-Li Chee Ji Chen Shyh-Huei Chen Yuan-Tsong Chen Zhengming Chen Lee-Ming Chuang Mary Cushman John Danesh Swapan K Das H Janaka de Silva George Dedoussis Latchezar Dimitrov Ayo P Doumatey Shufa Du Qing Duan Kai-Uwe Eckardt Leslie S Emery Daniel S Evans Michele K Evans Krista Fischer James S Floyd Ian Ford Oscar H Franco Timothy M Frayling Barry I Freedman Pauline Genter Hertzel C Gerstein Vilmantas Giedraitis Clicerio González-Villalpando Maria Elena González-Villalpando Penny Gordon-Larsen Myron Gross Lindsay A Guare Sophie Hackinger Liisa Hakaste Sohee Han Andrew T Hattersley Christian Herder Momoko Horikoshi Annie-Green Howard Willa Centre for Genetics and Genomics Versus Arthritis Centre for Musculoskeletal Research Division of Musculoskeletal and Dermatological Sciences University of Manchester Manchester UK. Department of Diabetes and Metabolic Diseases Graduate School of Medicine University of Tokyo Tokyo Japan. Department of Statistical Genetics Osaka University Graduate School of Medicine Suita Japan. Institute of Translational Genomics Helmholtz Zentrum München German Research Center for Environmental Health Neuherberg Germany. konstantinos.hatzikotoulas@helmholtz-munich.de. Institute of Translational Genomics Helmholtz Zentrum München German Research Center for Environmental Health Neuherberg Germany. Center for Precision Health Research National Human Genome Research Institute National Institutes of Health Bethesda MD USA. British Heart Foundation Cardiovascular Epidemiology Unit Department of Public Health and Primary Care University of Cambridge Cambridge UK. Heart and Lung Research Institute University of Cambridge Cambridge UK. Department of Epidemiology School of Public Health Nanjing Medical University Nanjing China. Department of Biostatistics and Center for Statistical Genetics University of Michigan Ann Arbor MI USA. Corporal Michael J. Crescenz VA Medical Center Philadelphia PA USA. Department of Systems Pharmacology and Translational Therapeutics University of Pennsylvania Perelman School of Medicine Philadelphia PA USA. Department of Genetics University of Pennsylvania Perelman School of Medicine Philadelphia PA USA. Programs in Metabolism and Medical and Population Genetics Broad Institute of Harvard and MIT Cambridge MA USA. Diabetes Unit and Center for Genomic Medicine Massachusetts General Hospital Boston MA USA. TIMI Study Group Division of Cardiovascular Medicine Brigham and Women's Hospital Harvard Medical School Boston MA USA. William Harvey Research Institute Barts and the London School of Medicine and Dentistry Queen Mary University of London L

Type 2 diabetes (T2D) is a heterogeneous disease that develops through diverse pathophysiological processes and molecular mechanisms that are often specific to cell type. Here, to characterize the genetic contribution to these processes across ancestry groups, we aggregate genome-wide association study data from 2,535,601 individuals (39.7% not of European ancestry), including 428,452 cases of T2D. We identify 1,289 independent association signals at genome-wide significance (P < 5 × 10) that map to 611 loci, of which 145 loci are, to our knowledge, previously unreported. We define eight non-overlapping clusters of T2D signals that are characterized by distinct profiles of cardiometabolic trait associations. These clusters are differentially enriched for cell-type-specific regions of open chromatin, including pancreatic islets, adipocytes, endothelial cells and enteroendocrine cells. We build cluster-specific partitioned polygenic scores in a further 279,552 individuals of diverse ancestry, including 30,288 cases of T2D, and test their association with T2D-related vascular outcomes. Cluster-specific partitioned polygenic scores are associated with coronary artery disease, peripheral artery disease and end-stage diabetic nephropathy across ancestry groups, highlighting the importance of obesity-related processes in the development of vascular outcomes. Our findings show the value of integrating multi-ancestry genome-wide association study data with single-cell epigenomics to disentangle the aetiological heterogeneity that drives the development and progression of T2D. This might offer a route to optimize global access to genetically informed diabetes care.

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Transcriptional Regulation of Cytotoxic T-Cell Responses in Acute Myeloid Leukemia

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Blood 2024年 144卷 5733-5733页

作者： Xufeng Chen Zhengxi Sun Jana Elegast Hua Zhou Soobeom Lee Deedra Nicolet Qiao Lu Kun Wang Jun Wang Wafa Al-Santli Ann-Kathrin Eisfeld Kimberly Stegmaier Iannis Aifantis Rebecca Austin Department of Pathology NYU Grossman School of Medicine New York NY Laura & Isaac Perlmutter Cancer Center NYU Langone New York NY Contributed equally * Dana-Farber Cancer Institute and Boston Children's Hospital Boston MA University and University Hospital Zurich Zurich Switzerland The Broad Institute of MIT and Harvard Cambridge MA New York University Grossman School of Medicine Applied Bioinformatics Laboratories New York NY Department of Biology New York University New York The Clara D. Bloomfield Center for Leukemia Outcomes Research The Ohio State University Comprehensive Cancer Center Columbus OH New York University Grossman School of Medicine NEW YORK NY NYU Grossman School of Medicine New York NY New York University Langone Health The Laura and Isaac Perlmutter Cancer Center New York NY The Ohio State University Columbus OH Pelotonia Institute for Immuno-Oncology OSUCCC - James The Ohio State University Columbus OH Alliance Statistics and Data Management Center The Ohio State University Comprehensive Cancer Center Columbus OH Division of Hematology Department of Internal Medicine The Ohio State University Wexner Medical Center Columbus OH Division of Hematology Department of Internal Medicine The Ohio State University Comprehensive Cancer Center Columbus OH Department of Pediatric Oncology Dana-Farber Cancer Institute Boston MA co-corresponding * Broad Institute of MIT and Harvard Cambridge MA New York University Grossman School of Medicine New York NY

Acute Myeloid Leukemia (AML) is an aggressive clonal hematopoietic neoplasm with an increased incidence in aged adults, a patient population who is often unfit to receive intensive cytotoxic induction chemotherapy and even alternative approved frontline regimes such as BH3 mimetics are often associated with high morbidity. Unfortunately, neither ICBs nor T cell-based cellular therapies are FDA-approved for treating AML. Recently, several TCR-T cells have shown moderate clinical activity in patients with AML. In such TCR-T studies, some patients do not respond and others develop acquired resistance. One potential reason for the low efficacy of immunotherapies in AML is that AML cells harbor a low mutational burden, which makes them less immunogenic. Moreover, AML can actively inhibit the MHC-I antigen presentation (AP) pathway, which determines recognition by CD8 + T cells and is essential for their activation and proliferation. Through hijacking this essential pathway, AML cells reduce their immunogenicity and avoid immune surveillance. These data are supported by clinical evidence that AML cells express low levels of the antigen presentation machinery (APM), especially at the time of relapse after conventional chemotherapies. In addition, several studies have demonstrated that AML cells may evade T-cell recognition by disrupting key pathways that modulate T-cell cytotoxicity, such as immune checkpoints and autophagy. However, the major contributors to the suppression of AML-associated T-cell cytotoxicity remain unknown. AML is also highly heterogeneous and aggressive, highlighting the difficulty of targeting this disease with a single therapeutic option. Combining or sequentially applying targeted therapy and immunotherapy might be a potential future strategy that could bypass mechanisms of resistance. Therefore, it is imperative to identify AML-specific regulators that potentiate T-cell cytotoxicity which could be combined with frontline therapies to offer more ef

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Organoid morphology-guided classification for oral cancer reveals prognosis

Cell Reports Medicine

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Cell Reports Medicine 2025年第5期6卷 102129-102129页

作者： Lee, Mi Rim Kang, Sumin Lee, Jonghyun Kong, Sun-Young Kim, Youngwook Lee, Yu-Sun Shon, Hye Won Kang, Gyeongmin Lee, Jiyoung Youn, Suk Min Kwack, Da Woon Park, Joo Yong Kim, Soung Min Choi, Wonyoung Lee, Jong-Ho Shin, Dongkwan Kwon, Ik-Jae Choi, Sung-Woen Kim, Yun-Hee Molecular Imaging Branch Division of Convergence Technology Research Institute of National Cancer Center 323 Ilsan-ro Ilsandong-gu Gyeonggi-do Goyang 10408 South Korea Department of Cancer Biomedical Science National Cancer Center Graduate School of Cancer Science and Policy 323 Ilsan-ro Ilsandong-gu Gyeonggi-do Goyang 10408 South Korea Bioinformatics Branch Division of Cancer Data Science Research Institute of National Cancer Center 323 Ilsan-ro Ilsandong-gu Gyeonggi-do Goyang 10408 South Korea Targeted Therapy Branch Division of Rare and Refractory Cancer Research Institute of National Cancer Center 323 Ilsan-ro Ilsandong-gu Gyeonggi-do Goyang 10408 South Korea Department of Laboratory Medicine National Cancer Center 323 Ilsan-ro Ilsandong-gu Gyeonggi-do Goyang 10408 South Korea Oral Oncology Clinic Research Institute and Hospital National Cancer Center 323 Ilsan-ro Ilsandong-gu Gyeonggi-do Goyang 10408 South Korea Department of Oral and Maxillofacial Surgery Seoul National University Dental Hospital Dental Research Institute School of Dentistry Seoul National University 101 Daehak-ro Jongno-gu Seoul 03080 South Korea Center for Clinical Trials Research Institute and Hospital National Cancer Center 323 Ilsan-ro Ilsandong-gu Gyeonggi-do Goyang 10408 South Korea Cancer Molecular Biology Branch Division of Cancer Biology Research Institute of National Cancer Center 323 Ilsan-ro Ilsandong-gu Gyeonggi-do Goyang 10408 South Korea Rare & Pediatric Cancer Branch Division of Rare and Refractory Cancer Research Institute of National Cancer Center 323 Ilsan-ro Ilsandong-gu Gyeonggi-do Goyang 10408 South Korea

Oral cancer is an aggressive malignancy with a survival rate below 50% in advanced stages due to low mutation rates, lack of molecular subtypes, and limited treatment targets. This study presents a pioneering approach to classifying oral cancer subtypes based on the morphology of patient-derived organoids (PDOs) and proposes a therapeutic strategy. We establish 76 cancer and 81 normal PDOs. For cancer PDOs, both manual classification and AI-based scoring are utilized to categorize them into three distinct subtypes: normal-like, dense, and grape-like. These subtypes correlate with unique transcriptomic profiles, genetic mutations, and clinical outcomes, with patients harboring dense and grape-like organoids exhibiting poorer prognoses. Furthermore, drug response assessments of 14 single agents and cisplatin combination therapies identify a synergistic treatment approach for resistant subtypes. This study highlights the potential of integrating morphology-based classification with genomic and transcriptomic analyses to refine oral cancer subtyping and develop effective treatment strategies. © 2025 The Author(s)

关键词： combination therapy morphology analysis oral cancer organoids

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Spatial and multiomics analysis of human and mouse lung adenocarcinoma precursors reveals TIM-3 as a putative target for precancer interception

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Cancer cell 2025年第6期43卷 1125-1140.e10页

作者： Bo Zhu Pingjun Chen Muhammad Aminu Jian-Rong Li Junya Fujimoto Yanhua Tian Lingzhi Hong Hong Chen Xin Hu Chenyang Li Natalie Vokes Andre L Moreira Don L Gibbons Luisa M Solis Soto Edwin Roger Parra Cuentas Ou Shi Songhui Diao Jie Ye Frank R Rojas Eduardo Vilar Anirban Maitra Ken Chen Nicolas Navin Monique Nilsson Beibei Huang Simon Heeke Jianhua Zhang Cara L Haymaker Vamsidhar Velcheti Daniel H Sterman Veena Kochat William I Padron Ludmil B Alexandrov Zhubo Wei Xiuning Le Linghua Wang Junya Fukuoka J Jack Lee Ignacio I Wistuba Harvey I Pass Mark Davis Samir Hannash Chao Cheng Steven Dubinett Avrum Spira Kunal Rai Scott M Lippman P Andrew Futreal John V Heymach Alexandre Reuben Jia Wu Jianjun Zhang Department of Thoracic/Head and Neck Medical Oncology The University of Texas MD Anderson Cancer Center Houston TX USA Department of Genomic Medicine The University of Texas MD Anderson Cancer Center Houston TX USA. Institute for Data Science in Oncology The University of Texas MD Anderson Cancer Center Houston TX USA Department of Translational Molecular Pathology The University of Texas MD Anderson Cancer Center Houston TX USA. Department of Imaging Physics The University of Texas MD Anderson Cancer Center Houston TX USA. Department of Medicine Baylor College of Medicine Houston TX USA. Clinical Research Center in Hiroshima Hiroshima University Hospital Hiroshima Japan. Department of Thoracic/Head and Neck Medical Oncology The University of Texas MD Anderson Cancer Center Houston TX USA. Department of Pathology NYU Langone Health New York NY USA. Department of Clinical Cancer Prevention The University of Texas MD Anderson Cancer Center Houston TX USA. Department of Translational Molecular Pathology and Sheikn Ahmed Center for Pancreatic Cancer Research The University of Texas MD Anderson Cancer Center Houston TX USA. Department of Bioinformatics and Computational Biology The University of Texas MD Anderson Cancer Center Houston TX USA. Department of Systems Biology The University of Texas MD Anderson Cancer Center Houston TX USA. Department of Cancer Systems Imaging The University of Texas MD Anderson Cancer Center Houston TX USA. Department of Medicine NYU Grossman School of Medicine New York NY USA. Department of Medicine NYU Grossman School of Medicine New York NY USA Cardiothoracic Surgery NYU Grossman School of Medicine New York NY USA. Department of Cellular and Molecular Medicine UC San Diego La Jolla CA USA. Department of Pathology Informatics Nagasaki University Graduate School of Biomedical Sciences Nagasaki Japan. Department of Biostatistics The University of Texas MD Anderson Cancer Center Houston TX USA. Department of Car

How tumor microenvironment shapes lung adenocarcinoma (LUAD) precancer evolution remains poorly understood. Spatial immune profiling of 114 human LUAD and LUAD precursors reveals a progressive increase of adaptive response and a relative decrease of innate immune response as LUAD precursors progress. The immune evasion features align the immune response patterns at various stages. TIM-3-high features are enriched in LUAD precancers, which decrease in later stages. Furthermore, single-cell RNA sequencing (scRNA-seq) and spatial immune and transcriptomics profiling of LUAD and LUAD precursor specimens from 5 mouse models validate high TIM-3 features in LUAD precancers. In vivo TIM-3 blockade at precancer stage, but not at advanced cancer stage, decreases tumor burden. Anti-TIM-3 treatment is associated with enhanced antigen presentation, T cell activation, and increased M1/M2 macrophage ratio. These results highlight the coordination of innate and adaptive immune response/evasion during LUAD precancer evolution and suggest TIM-3 as a potential target for LUAD precancer interception.

关键词： TIM-3 cancer prevention imaging mass cytometry immune landscape lung adenocarcinoma evolution precancer spatial single cell stage dependent

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Correction to: Effect of early tumor response on the health-related quality of life among patients on second-line chemotherapy for advanced gastric cancer in the ABSOLUTE trial

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Gastric cancer : official journal of the International Gastric Cancer Association and the Japanese Gastric Cancer Association 2021年第2期24卷 477-478页

作者： Kazumasa Fujitani Kohei Shitara Atsuo Takashima Keisuke Koeda Hiroki Hara Norisuke Nakayama Shuichi Hironaka Kazuhiro Nishikawa Yutaka Kimura Kenji Amagai Hisashi Hosaka Yoshito Komatsu Ken Shimada Ryohei Kawabata Hideki Ohdan Yasuhiro Kodera Masato Nakamura Takako Eguchi Nakajima Yoshinori Miyata Toshikazu Moriwaki Tetsuya Kusumoto Kazuo Nishikawa Kazuhiro Ogata Masashi Shimura Satoshi Morita Wasaburo Koizumi Department of Surgery Osaka General Medical Center 3-1-56 Bandaihigashi Sumiyoshi-ku Osaka 558-0056 Japan. fujitani@gh.opho.jp. Department of Gastrointestinal Oncology National Cancer Center Hospital East Kashiwa Japan. Gastrointestinal Medical Oncology Division National Cancer Center Hospital Tokyo Japan. Department of Medical Safety Science Iwate Medical University Morioka Japan. Department of Gastroenterology Saitama Cancer Center Ina-machi Japan. Department of Gastroenterology Kanagawa Cancer Center Yokohama Japan. Clinical Trial Promotion Department Chiba Cancer Center Chiba Japan. Department of Medical Oncology and Hematology Faculty of Medicine Oita University Oita Japan. Department of Surgery National Hospital Organization Osaka National Hospital Osaka Japan. Department of Surgery Sakai City Medical Center Sakai Japan. Department of Gastroenterology Ibaraki Prefectural Central Hospital Kasama Japan. Division of Gastroenterology Gunma Prefectural Cancer Center Ohta Japan. Division of Cancer Chemotherapy Hokkaido University Hospital Cancer Center Sapporo Japan. Division of Medical Oncology Department of Internal Medicine Showa University Northern Yokohama Hospital Yokohama Japan. Department of Surgery Osaka Rosai Hospital Osaka Japan. Department of Gastroenterological and Transplant Surgery Graduate School of Biomedical and Health Sciences Hiroshima University Hiroshima Japan. Department of Gastroenterological Surgery Nagoya University Graduate School of Medicine Nagoya Japan. Aizawa Comprehensive Cancer Center Aizawa Hospital Nagano Japan. Department of Clinical Oncology St. Marianna University School of Medicine Kawasaki Japan. Kyoto Innovation Center for Next Generation Clinical Trials and iPS Cell Therapy Kyoto University Hospital Kyoto Japan. Department of Medical Oncology Saku Central Hospital Advanced Care Center Saku Japan. Division of Gastroenterology Faculty of Medicine University of Tsukuba Tsukuba Japan. Department of Gast

The article Effect of early tumor response on the health-related quality of life among patients.

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Repurposing of PI3K inhibitors for high-grade serous ovarian cancer: A novel competing endogenous network analysis-based approach

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Computers in biology and medicine 2025年 194卷 110471页

作者： Anna Erol Karolina Chwialkowska Anna Zeller Anna Skwarska Agnieszka Ostrowska Gabriela Sokolowska Katarzyna Doroszko Iwona Sidorkiewicz Justyna Raczkowska Damian Toczydlowski Anna Michalska-Falkowska Mariusz Kuzmicki Jacek Szamatowicz Joanna Gielazyn-Reszec Michał Ryn Paweł Knapp Marcin Moniuszko Adam Kretowski Magdalena Niemira Clinical Research Centre Medical University of Bialystok Bialystok Poland. Electronic address: anna.erol@umb.edu.pl. Centre for Bioinformatics and Data Analysis Medical University of Bialystok Bialystok Poland. Clinical Research Centre Medical University of Bialystok Bialystok Poland. Montefiore-Einstein Comprehensive Cancer Center Albert Einstein College of Medicine Bronx NY USA. Biobank Medical University of Bialystok Bialystok Poland. Department of Gynecology and Gynecological Oncology Medical University of Bialystok Bialystok Poland. Department of Medical Pathomorphology Medical University of Bialystok Bialystok Poland. University Oncology Center Medical University of Bialystok Bialystok Poland. Department of Regenerative Medicine and Immune Regulation Medical University of Bialystok Bialystok Poland. Clinical Research Centre Medical University of Bialystok Bialystok Poland Department of Endocrinology Diabetology and Internal Medicine Medical University of Bialystok Bialystok Poland.

INTRODUCTION:The average survival time for High-Grade Serous Ovarian Cancer (HGSOC) is around 3.4 years post-diagnosis. The treatment options are limited, especially for relapsed patients, resistant to standard treatment. Therefore, novel drug candidates are needed. OBJECTIVE:We propose a novel approach for predicting potential drug candidates by focusing on agents capable of reversing the effects of perturbed RNA network. METHODS:The competing endogenous RNA (ceRNAs) network was constructed on differential expression (DE) of long non-coding RNAs (lncRNAs), protein-coding RNAs (mRNAs) and microRNAs (miRNAs) from the primary HGSOC tumour tissues. It allowed for identification of key perturbed axes of RNA regulation. The publicly available resources for drug repurposing were used to select candidates for in-vitro validation. RESULTS:The phosphoinositide 3-kinase (PI3K) pathway, known to be involved in developing drug resistance in ovarian cancer, was identified as highly dependent from the coding and non-coding RNA interactions. PI3K pathway inhibitors, PI-103 and ZSTK474, were identified as drug candidates and their efficacy against HGSOC was confirmed in vitro. E2F1 and SNAI2 are essential transcription factors (TFs) known for regulating critical cancer pathways such as cell cycle repair or epithelial-mesenchymal transition (EMT). In our study, these TFs were identified as hub regulators within the ceRNA network. CONCLUSION:Investigation of fine-tune regulation of RNA by non-coding RNAs and TFs uncovered a significant role of ceRNA network in cancer development, highlighting its integration with master regulatory pathways that drive tumor progression and sustainability. The drug repurposing workflow based on ceRNA-limited differentially expressed mRNAs allowed for effective prioritization of compounds with potential to be applied as treatment.

关键词： Competing endogenous network Drug repurposing High-grade serous ovarian cancer PI3K inhibitor

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Author Correction: Massively parallel interrogation of protein fragment secretability using SECRiFY reveals features influencing secretory system transit

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Nature communications 2023年第1期14卷 1072页

作者： Morgane Boone Pathmanaban Ramasamy Jasper Zuallaert Robbin Bouwmeester Berre Van Moer Davy Maddelein Demet Turan Niels Hulstaert Hannah Eeckhaut Elien Vandermarliere Lennart Martens Sven Degroeve Wesley De Neve Wim Vranken Nico Callewaert Center for Medical Biotechnology VIB Zwijnaarde Belgium. morganeboone@***. Department of Biochemistry and Microbiology Faculty of Sciences Ghent University Ghent Belgium. morganeboone@***. Department of Biochemistry and Biophysics UCSF San Francisco CA USA. morganeboone@***. Center for Medical Biotechnology VIB Zwijnaarde Belgium. Department of Biomolecular Medicine Faculty of Medicine and Health Sciences Ghent University Ghent Belgium. Structural Biology Brussels VUB Brussels Belgium. Structural Biology Research Center VIB Brussels Belgium. Interuniversity Institute of Bioinformatics in Brussels (IB)2 ULB-VUB Brussels Belgium. Department of Biochemistry and Microbiology Faculty of Sciences Ghent University Ghent Belgium. Center for Biotech Data Science Ghent University Global Campus Songdo Incheon South Korea. IDLab ELIS UGent Ghent Belgium. Center for Medical Biotechnology VIB Zwijnaarde Belgium. nico.callewaert@vib-ugent.be. Department of Biochemistry and Microbiology Faculty of Sciences Ghent University Ghent Belgium. nico.callewaert@vib-ugent.be.

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The repertoire of mutational signatures in human cancer (vol 578, pg 94, 2020)

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NATURE 2023年第7948期614卷 E41-E41页

作者： Alexandrov, Ludmil B. Kim, Jaegil Haradhvala, Nicholas J. Huang, Mi Ni Ng, Alvin Wei Tian Wu, Yang Boot, Arnoud Covington, Kyle R. Gordenin, Dmitry A. Bergstrom, Erik N. Islam, S. M. Ashiqul Lopez-Bigas, Nuria Klimczak, Leszek J. McPherson, John R. Morganella, Sandro Sabarinathan, Radhakrishnan Wheeler, David A. Mustonen, Ville Getz, Gad Rozen, Steven G. Stratton, Michael R. Department of Cellular and Molecular Medicine Department of Bioengineering Moores Cancer Center University of California San Diego CA USA Wellcome Sanger Institute Wellcome Genome Campus Hinxton UK Department of Cellular and Molecular Medicine and Department of Bioengineering University of California San Diego La Jolla CA USA UC San Diego Moores Cancer Center San Diego CA USA University of California San Diego San Diego CA USA Broad Institute of MIT and Harvard Cambridge MA USA Center for Cancer Research Massachusetts General Hospital Boston MA USA Massachusetts General Hospital Boston MA USA Department of Pathology Massachusetts General Hospital Boston MA USA Harvard Medical School Boston MA USA Laboratory for Medical Science Mathematics RIKEN Center for Integrative Medical Sciences Yokohama Japan Computational Biology Program Ontario Institute for Cancer Research Toronto ON Canada Programme in Cancer & Stem Cell Biology Duke-NUS Medical School Singapore Singapore Centre for Computational Biology Duke-NUS Medical School Singapore Singapore Programme in Cancer and Stem Cell Biology Duke-NUS Medical School Singapore Singapore Programme in Cancer and Stem Cell Biology Centre for Computational Biology Duke-NUS Medical School Singapore Singapore SingHealth Duke-NUS Institute of Precision Medicine National Heart Centre Singapore Singapore Singapore Cancer Science Institute of Singapore National University of Singapore Singapore Singapore Institute of Molecular and Cell Biology Singapore Singapore Laboratory of Cancer Epigenome Division of Medical Science National Cancer Centre Singapore Singapore Singapore Duke-NUS Medical School Singapore Singapore Human Genome Sequencing Center Baylor College of Medicine Houston TX USA Dan L. Duncan Cancer Center Baylor College of Medicine Houston TX USA Department of Molecular and Human Genetics Baylor College of Medicine Houston TX USA Genome Integrity and Structural Biology Laboratory National Ins

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POS0100 TARGETING NF-ΚB SIGNALLING IN B LINEAGE CELLS AS A POTENTIAL NOVEL TREATMENT STRATEGY FOR ANCA-ASSOCIATED VASCULITIS

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Annals of the Rheumatic Diseases 2023年 82卷 263-263页

作者： A. Merino-Vico J.P. Van Hamburg C. Bonasia P. Heeringa P. Tuijnenburg B. Helder M. Jansen A. Al-Soudi H.K. Olsson N. De Vries C. Stegeman J.S. Sanders A. Rutgers W. Abdulahad P. Lyons T. Bijma A. Jongejan T.W. Kuijpers S. Tas Amsterdam Rheumatology & immunology Center Amsterdam UMC/University of Amsterdam Department of Rheumatology and Clinical Immunology Amsterdam Netherlands Amsterdam UMC/University of Amsterdam Department of Experimental Immunology Amsterdam Netherlands University Medical Center Groningen Groningen the Netherlands Department of Rheumatology and Clinical Immunology Groningen Netherlands University Medical Center Groningen Groningen the Netherlands Department of Pathology and Medical Biology Groningen Netherlands Emma Children's Hospital Amsterdam UMC University of Amsterdam Department of Pediatric Immunology Rheumatology and Infectious diseases Amsterdam Netherlands AstraZeneca AstraZeneca Gothenburg Sweden Gothenburg Sweden University Medical Center Groningen Groningen the Netherlands Dept of Internal Medicine Division of Nephrology Groningen Netherlands University pf Cambridge School of Clinical Medicine University of Cambridge Dept of Medicine Cambridge United Kingdom Amsterdam Public Health Research Institute Amsterdam UMC University of Amsterdam Department of Epidemiology and Data Science Bioinformatics Laboratory Amsterdam Netherlands Sanquin Amsterdam Amsterdam & Department of Blood Cell Research Amsterdam Netherlands Academic Medical Center (AMC) Department of Pediatrics Amsterdam Netherlands

Background B cells are crucially important in the pathogenesis of many autoimmune diseases, including ANCA-associated vasculitis (AAV), which is further demonstrated by the beneficial clinical effects of rituximab (anti-CD20) B cell targeted therapy. Despite its advantages, this treatment strategy results in long-term B cell depletion and fails to target long-lived plasma cells, rendering an unmet need for more reversible and combined B and plasma cell targeting approaches to achieve long-term disease remission. This aim may be reached by targeting signalling pathways essential for different B cell functions. The canonical and non-canonical NF-κB signalling pathways regulate fundamental B and/or plasma cell responses downstream of various B cell surface receptors, including the B cell receptor, CD40, and TLRs. Objectives To study potential alterations in NF-κB signalling in B lineage cells and to evaluate the effects of targeting NF-κB on B cell responses in general, and more specifically on proliferation, plasmablast differentiation and (auto)antibody production in B cells from AAV patients. Methods Memory B cells were obtained from AAV patients and healthy donors (HD), and gene expression profiles were generated by RNA-sequencing. Functional assays were performed by culturing PMBCs from AAV patients and HD with stimuli mimicking T cell-dependent (anti-CD40/IL-21) and T cell-independent (CpG/IL-2) conditions. Pharmacological inhibitors of Inhibitor-of-κB-kinase-β (IKKβ, canonical pathway) or NF-κB inducing kinase (NIK, non-canonical pathway) were added to the cultures. Downstream NF-κB signalling was determined by Western blot. After 6-day cultures, B cell proliferation and differentiation were determined by flow cytometry, and ELISA was performed for the detection of (auto)antibody production. Results Memory B cells from AAV patients with active disease exhibited an increased expression of NF-κB-associated genes compared to patients in remission and HD. Targeting

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Assessment of protein assembly prediction in CASP13

arXiv

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arXiv 2019年

作者： Guzenko, Dmytro Lafita, Aleix Monastyrskyy, Bohdan Kryshtafovych, Andriy Duarte, Jose M. Research Collaboratory for Structural Bioinformatics Protein Data Bank San Diego Supercomputer Center University of California San Diego La JollaCA92093 United States European Molecular Biology Laboratory European Bioinformatics Institute Wellcome Genome Campus Hinxton CambridgeCB10 1SD United Kingdom Protein Structure Prediction Center Genome and Biomedical Sciences Facilities University of California DavisCA95616 United States

We present the assembly category assessment in the 13th edition of the CASP community-wide experiment. For the second time, protein assemblies constitute an independent assessment category. Compared to the last edition we see a clear uptake in participation, more oligomeric targets released, and consistent, albeit modest, improvement of the predictions quality. Looking at the tertiary structure predictions we observe that ignoring the oligomeric state of the targets hinders modelling success. We also note that some contact prediction groups successfully predicted homomeric interfacial contacts, though it appears that these predictions were not used for assembly modelling. Homology modelling with sizeable human intervention appears to form the basis of the assembly prediction techniques in this round of CASP. Future developments should see more integrated approaches to modelling where multiple subunits are a natural part of the modelling process, which would benefit the structure prediction field as a whole. K E Y W O R D S CASP, protein assembly, protein interfaces, structure prediction Copyright © 2019, The Authors. All rights reserved.

关键词： Forecasting

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