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Leukemia Evolution and Resistance to Graft-Versus-Leukemia Responses Revealed By Mitochondrial DNA Mutations

Blood 2024年 144卷 926-926页

作者： Livius Penter Nicoletta Cieri Katie Maurer Marwan Kwok Haoxiang Lyu Wesley S Lu Giacomo Oliveira Satyen H Gohil Ignaty Leshchiner Caleb Lareau Leif S Ludwig Donna S. Neuberg Haesook T. Kim Shuqiang Li Lars Bullinger Jerome Ritz Gad Getz Jacqueline S. Garcia Robert J. Soiffer Kenneth J. Livak Catherine J. Wu Department of Hematology Oncology and Cancer Immunology Campus Virchow Klinikum Charité - Universitätsmedizin Berlin Berlin Germany Department of Medical Oncology Dana-Farber Cancer Institute Berlin Germany Harvard Medical School Boston MA Broad Institute of MIT and Harvard Cambridge MA Department of Medical Oncology Dana-Farber Cancer Institute Boston MA Institute of Cancer and Genomic Sciences University of Birmingham Bimingham United Kingdom Institute of Cancer and Genomic Sciences University of Birmingham Birmingham United Kingdom Queen Elizabeth Hospital Birmingham Centre for Clinical Haematology Birmingham United Kingdom Translational Immunogenomics Lab Dana-Farber Cancer Institute Boston MA Haematology University College Hospital London United Kingdom Cancer Program Broad Institute of MIT and Harvard Cambridge MA Memorial Sloan Kettering Cancer Center New York NY Berlin Institute of Health at Charité - Universitätsmedizin Berlin Berlin Germany Department of Data Science Dana-Farber Cancer Institute Boston MA Department of Hematology Oncology and Cancer Immunology Charité - Universitätsmedizin Berlin Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin and Berlin Institute of Health Berlin Germany Department of Pathology Massachusetts General Hospital Boston MA

Graft-versus-leukemia (GvL) responses enable successful allogeneic hematopoietic cell transplantation (HCT), a cornerstone treatment for high-risk blood cancers such as acute myeloid leukemia (AML) or advanced chronic lymphocytic leukemia (CLL). Yet, monitoring of GvL effects remains challenging, including early detection of emerging immune escape or tracking of clonal evolution during phases of incomplete leukemia control. We hypothesized that mitochondrial DNA (mtDNA) mutation analysis would be an effective tool for sensitive monitoring of clonal evolution and measurable residual disease (MRD) that could yield new insights into the dynamics and cellular phenotypes of GvL response or resistance. To establish mtDNA mutations as natural genetic barcodes capable of resolving leukemic evolution, we analyzed 126 serially collected bulk RNA and whole-exome sequencing (WES) datasets of CD19 + sorted CLL cells from 34 individuals (median interval first-to-last sample 2,184 days, range 280-4,402). We discerned high correlation between changes in heteroplasmy of mtDNA mutations (RNA-seq) and cancer cell fraction (CCF, calculated from WES data) (r=0.84; p<0.001). In particular, heteroplasmy and CCF changes were smaller in genetically stable (n=8) compared to evolving (n=18) CLL (coefficient of variation 24 vs 60 [heteroplasmy] and 31 vs 57 [CCF]; p<0.001). Following HCT (n=8), shorter vs longer days-to-relapse (median 310 vs 1,082) was associated with lesser vs more changes in heteroplasmy (p=0.034), suggesting the ability to measure cumulative GvL effects with mtDNA mutations. In 3 cases, we obtained single cell (sc) DNA-seq profiles (Tapestri) from circulating CLL before and after HCT and directly detected co-evolution of somatic nuclear with mtDNA mutations. Thus, mtDNA mutations track with leukemia clones and their dynamics are highly consistent with changes in somatic nuclear DNA mutations. To assess mtDNA mutations as sensitive markers of MRD, we determined their median

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Comparative analyses for plant virus-based cancer immunotherapy drug development

Cell Biomaterials

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Cell Biomaterials 2025年

作者： Anthony O. Omole Hannah S. Newton Edward Cedrone Kimia Nematpour Shaojun Xie Yongmei Zhao Bao Tran Marina A. Dobrovolskaia Nicole F. Steinmetz Aiiso Yufeng Li Family Department of Chemical and Nano Engineering University of California San Diego La Jolla San Diego CA 92093 USA Shu and K.C. Chien and Peter Farrell Collaboratory University of California San Diego La Jolla San Diego CA 92093 USA Center for Nano-ImmunoEngineering University of California San Diego La Jolla San Diego CA 92093 USA Moores Cancer Center University of California San Diego La Jolla San Diego CA 92093 USA Nanotechnology Characterization Lab Cancer Research Technology Program Frederick National Laboratory for Cancer Research sponsored by the National Cancer Institute Frederick MD 21702 USA Sequencing Facility Bioinformatics Group Biomedical Informatics and Data Science Directorate Frederick National Laboratory for Cancer Research sponsored by the National Cancer Institute Frederick MD 21702 USA CCR Sequencing Facility Cancer Research Technology Program Frederick National Laboratory for Cancer Research sponsored by the National Cancer Institute Frederick MD 21702 USA Department of Bioengineering University of California San Diego La Jolla San Diego CA 92093 USA Department of Radiology University of California San Diego La Jolla San Diego CA USA Institute for Materials Discovery and Design University of California San Diego La Jolla San Diego CA 92093 USA Center for Engineering in Cancer Institute of Engineering Medicine University of California San Diego La Jolla San Diego CA 92093 USA

Cowpea mosaic virus (CPMV) is a plant virus with potent anti-tumor efficacy. Intratumoral CPMV, but not cowpea chlorotic mottle virus (CCMV), reprograms the tumor microenvironment priming durable, systemic anti-tumor immunity. Here, we performed a side-by-side mechanism of action comparison between CPMV and CCMV. Through immune-multiplexing and trafficking studies we observed that CPMV and CCMV are taken up by innate immune cells at similar rates but are processed differently. While CCMV induces proinflammatory interleukins 22, 23, and 27, CPMV is a strong inducer of type I, II, and III interferons, which contribute to the activation and enhancement of immune cell function. We observed that CPMV RNAs activate Toll-like receptor (TLR) 7 upon delivery—and not CCMV RNAs; CPMV RNAs persist longer within cells compared with CCMV. Taken together, this work identifies determinants for CPMV’s unique mechanism for intratumoral immunotherapy. It also broadens our understanding of the utility of plant viruses for biomedical applications.

关键词： plant viruses intratumoral immunotherapy cowpea mosaic virus cowpea chlorotic mottle virus cancer nanotechnology

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Patterns of somatic structural variation in human cancer genomes (vol 578, pg 112, 2020)

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NATURE 2023年第7948期614卷 E38-E38页

作者： Li, Yilong Roberts, Nicola D. Wala, Jeremiah A. Shapira, Ofer Schumacher, Steven E. Kumar, Kiran Khurana, Ekta Waszak, Sebastian Korbel, Jan O. Haber, James E. Imielinski, Marcin Weischenfeldt, Joachim Beroukhim, Rameen Campbell, Peter J. Cancer Genome Project Wellcome Trust Sanger Institute Hinxton UK Totient Inc Cambridge MA USA Wellcome Sanger Institute Wellcome Genome Campus Hinxton UK Department of Haematology University of Cambridge Cambridge UK Cambridge University Hospitals NHS Foundation Trust Cambridge UK Korea Advanced Institute of Science and Technology Daejeon South Korea Department of Zoology Genetics and Physical Anthropology University of Santiago de Compostela Santiago de Compostela Spain Centre for Research in Molecular Medicine and Chronic Diseases (CIMUS) University of Santiago de Compostela Santiago de Compostela Spain The Biomedical Research Centre (CINBIO) University of Vigo Vigo Spain Centre for Research in Molecular Medicine and Chronic Diseases (CiMUS) Universidade de Santiago de Compostela Santiago de Compostela Spain Department of Zoology Genetics and Physical Anthropology (CiMUS) Universidade de Santiago de Compostela Santiago de Compostela Spain The Biomedical Research Centre (CINBIO) Universidade de Vigo Vigo Spain The Broad Institute of Harvard and MIT Cambridge MA USA Bioinformatics and Integrative Genomics Harvard University Cambridge MA USA Department of Cancer Biology Dana-Farber Cancer Institute Boston MA USA Broad Institute of MIT and Harvard Cambridge MA USA Department of Medical Oncology Dana-Farber Cancer Institute Boston MA USA Harvard Medical School Boston MA USA Massachusetts General Hospital Center for Cancer Research Charlestown MA USA Dana-Farber Cancer Institute Boston MA USA Department of Biostatistics and Computational Biology Dana-Farber Cancer Institute and Harvard Medical School Boston MA USA Weill Cornell Medical College New York NY USA Department of Physiology and Biophysics Weill Cornell Medicine New York NY USA Institute for Computational Biomedicine Weill Cornell Medicine New York NY USA Controlled Department and Institution New York NY USA Englander Institute for Precision Medicine Weill Cornell Medicine Ne

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Correction: Polygenic risk modeling for prediction of epithelial ovarian cancer risk

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European journal of human genetics : EJHG 2022年第5期30卷 630-631页

作者： Eileen O Dareng Jonathan P Tyrer Daniel R Barnes Michelle R Jones Xin Yang Katja K H Aben Muriel A Adank Simona Agata Irene L Andrulis Hoda Anton-Culver Natalia N Antonenkova Gerasimos Aravantinos Banu K Arun Annelie Augustinsson Judith Balmaña Elisa V Bandera Rosa B Barkardottir Daniel Barrowdale Matthias W Beckmann Alicia Beeghly-Fadiel Javier Benitez Marina Bermisheva Marcus Q Bernardini Line Bjorge Amanda Black Natalia V Bogdanova Bernardo Bonanni Ake Borg James D Brenton Agnieszka Budzilowska Ralf Butzow Saundra S Buys Hui Cai Maria A Caligo Ian Campbell Rikki Cannioto Hayley Cassingham Jenny Chang-Claude Stephen J Chanock Kexin Chen Yoke-Eng Chiew Wendy K Chung Kathleen B M Claes Sarah Colonna Linda S Cook Fergus J Couch Mary B Daly Fanny Dao Eleanor Davies Miguel de la Hoya Robin de Putter Joe Dennis Allison DePersia Peter Devilee Orland Diez Yuan Chun Ding Jennifer A Doherty Susan M Domchek Thilo Dörk Andreas du Bois Matthias Dürst Diana M Eccles Heather A Eliassen Christoph Engel Gareth D Evans Peter A Fasching James M Flanagan Renée T Fortner Eva Machackova Eitan Friedman Patricia A Ganz Judy Garber Francesca Gensini Graham G Giles Gord Glendon Andrew K Godwin Marc T Goodman Mark H Greene Jacek Gronwald Eric Hahnen Christopher A Haiman Niclas Håkansson Ute Hamann Thomas V O Hansen Holly R Harris Mikael Hartman Florian Heitz Michelle A T Hildebrandt Estrid Høgdall Claus K Høgdall John L Hopper Ruea-Yea Huang Chad Huff Peter J Hulick David G Huntsman Evgeny N Imyanitov Claudine Isaacs Anna Jakubowska Paul A James Ramunas Janavicius Allan Jensen Oskar Th Johannsson Esther M John Michael E Jones Daehee Kang Beth Y Karlan Anthony Karnezis Linda E Kelemen Elza Khusnutdinova Lambertus A Kiemeney Byoung-Gie Kim Susanne K Kjaer Ian Komenaka Jolanta Kupryjanczyk Allison W Kurian Ava Kwong Diether Lambrechts Melissa C Larson Conxi Lazaro Nhu D Le Goska Leslie Jenny Lester Fabienne Lesueur Douglas A Levine Lian Li Jingmei Li Jennifer T Loud Karen H Lu Jan Lubiński Phuong L Mai Siranoush Manoukian Jeffrey R Marks Ra University of Cambridge Centre for Cancer Genetic Epidemiology Department of Public Health and Primary Care Cambridge UK. University of Cambridge Centre for Cancer Genetic Epidemiology Department of Oncology Cambridge UK. Center for Bioinformatics and Functional Genomics Cedars-Sinai Medical Center Los Angeles CA USA. Radboud University Medical Center Radboud Institute for Health Sciences Nijmegen The Netherlands. Netherlands Comprehensive Cancer Organisation Utrecht The Netherlands. The Netherlands Cancer Institute-Antoni van Leeuwenhoek hospital Family Cancer Clinic Amsterdam The Netherlands. Veneto Institute of Oncology IOV-IRCCS Immunology and Molecular Oncology Unit Padua Italy. Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital Fred A. Litwin Center for Cancer Genetics Toronto ON Canada. University of Toronto Department of Molecular Genetics Toronto ON Canada. University of California Irvine Department of Epidemiology Genetic Epidemiology Research Institute Irvine CA USA. N.N. Alexandrov Research Institute of Oncology and Medical Radiology Minsk Belarus. 'Agii Anargiri' Cancer Hospital Athens Greece. University of Texas MD Anderson Cancer Center Department of Breast Medical Oncology Houston TX USA. Lund University Department of Cancer Epidemiology Clinical Sciences Lund Sweden. Vall d'Hebron Institute of Oncology Hereditary cancer Genetics Group Barcelona Spain. University Hospital of Vall d'Hebron Department of Medical Oncology Barcelona Spain. Rutgers Cancer Institute of New Jersey Cancer Prevention and Control Program New Brunswick NJ USA. Landspitali University Hospital Department of Pathology Reykjavik Iceland. University of Iceland BMC (Biomedical Centre) Faculty of Medicine Reykjavik Iceland. University Hospital Erlangen Friedrich-Alexander-University Erlangen-Nuremberg Department of Gynecology and Obstetrics Comprehensive Cancer Center ER-EMN Erlangen Germany. Vanderbilt University School of Medicine Division of Epide

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Publisher Correction: A T cell resilience model associated with response to immunotherapy in multiple tumor types

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Nature medicine 2022年第10期28卷 2219页

作者： Yu Zhang Trang Vu Douglas C Palmer Rigel J Kishton Lanqi Gong Jiao Huang Thanh Nguyen Zuojia Chen Cari Smith Ferenc Livák Rohit Paul Chi-Ping Day Chuan Wu Glenn Merlino Kenneth Aldape Xin-Yuan Guan Peng Jiang Cancer Data Science Laboratory Center for Cancer Research National Cancer Institute National Institutes of Health Bethesda MD USA. Department of Clinical Oncology The University of Hong Kong Hong Kong China. Sun Yat-sen University Cancer Center State Key Laboratory of Oncology in South China Collaborative Innovation Center for Cancer Medicine Guangzhou China. Surgery Branch National Cancer Institute National Institutes of Health Bethesda MD USA. AstraZeneca Gaithersburg MD USA. Lyell Immunopharma South San Francisco CA USA. Laboratory of Pathology Center for Cancer Research National Cancer Institute National Institutes of Health Bethesda MD USA. Gaia Foods Singapore Singapore. Experimental Immunology Branch Center for Cancer Research National Cancer Institute National Institutes of Health Bethesda MD USA. Laboratory Animal Science Program Leidos Biomedical Research Inc Frederick MD USA. Flow Cytometry Core Center for Cancer Research National Cancer Institute National Institutes of Health Bethesda MD USA. Office of the Director Center for Cancer Research National Cancer Institute National Institutes of Health Bethesda MD USA. Laboratory of Cancer Biology and Genetics Center for Cancer Research National Cancer Institute National Institutes of Health Bethesda MD USA. Cancer Data Science Laboratory Center for Cancer Research National Cancer Institute National Institutes of Health Bethesda MD USA. peng.jiang@nih.gov.

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472P Homologous-recombination deficiency (HRD) in gastroesophageal adenocarcinoma (GEA): Clinical and molecular features

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Annals of Oncology 2024年 35卷 S189-S189页

作者： D. Acosta Eyzaguirre G. Castillo S. Aguilar Izquierdo M. Cruellas Lapena A. Herencia Ropero S. Landolfi H. Palma T. Tian A. Vivancos V. Serra Elizalde T. Macarulla Mercade Gastrointestinal and Endocrine Cancer Unit Vall d'Hebron University Hospital and Vall d'Hebron Institute of Oncology (VHIO) Barcelona Spain Oncology Data Science (ODysSey) Group Vall d'Hebron Institute of Oncology (VHIO) Barcelona Spain VHIOTECA & Prescreening Program Vall d'Hebron Institute of Oncology (VHIO) Barcelona Spain Clinical Cancer Genetics and Breast Cancer Group Vall d'Hebron University Hospital Barcelona Spain Experimental Therapeutics Department Vall d'Hebron Institute of Oncology (VHIO) Barcelona Spain Department of Pathological Anatomy Vall d'Hebron University Hospital Barcelona Spain Medical Oncology Department Vall d'Hebron Institute of Oncology (VHIO) Barcelona Spain Upper GI Cancer Translational Research Group Vall d'Hebron Institute of Oncology (VHIO) Barcelona Spain Cancer Genomics Group Vall d'Hebron Institute of Oncology (VHIO) Barcelona Spain Gastrointestinal and Endocrine Cancer Unit and Upper GI Cancer Translational Research Group Vall d'Hebron University Hospital and Vall d'Hebron Institute of Oncology (VHIO) Barcelona Spain

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Treatment Outcomes By Duffy Genotype in Patients (Pts) with Newly Diagnosed Multiple Myeloma (NDMM) Receiving Lenalidomide, Bortezomib, and Dexamethasone (RVd) Alone or Rvd Plus Autologous Stem Cell Transplantation (ASCT) in the Determination Phase 3 Trial

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Transplantation and Cellular Therapy 2025年第2期31卷 S406-S407页

作者： Merz, Lauren E., MD Zon, Rebecca L., MD Jacobus, Susanna J, MSc, MBA Samur, Mehmet K., PhD Zonder, Jeffrey, MD Khan, Dr. Abdullah Mohammad Hassoun, Hani, MD Anderson, Larry D., MD, PhD Efebera, Yvonne, MD Buck, Tondre, MD Shelton, Racquel D. Innis Hartley-Brown, Monique A., MD Lonial, Sagar, MD, FACP Campagnaro, Erica L., MD Voorhees, Peter M. Orlowski, Robert Z., MD, PhD Libby, Edward N., MD Hurd, David D, MD Costello, Caitlin, MD Raje, Noopur S., MD Medvedova, Eva, MD McCarthy, Philip L., MD Milner, Carter P., MD Gasparetto, Cristina, MD Agha, Mounzer E., MD Gowin, Krisstina, DO Kamble, Rammurti T., MD Jagannath, Sundar, MD Nathwani, Nitya, MD Alsina, Melissa, MD Giralt, Sergio A., MD Laubach, Jacob P., MD Nadeem, Omar, MD Ghobrial, Irene M., MD Mo, Clifton C., MD Anderson, Kenneth C., MD Munshi, Nikhil C., MD Richardson, Paul G., MD Department of Medical Oncology Dana-Farber Cancer Institute Harvard Medical School Boston MA Division of Hematology/Oncology Mass General Brigham Boston MA Department of Data Science Dana-Farber Cancer Institute Harvard Medical School Boston MA Barbara Ann Karmanos Cancer Institute / Wayne State University School of Medicine Detroit MI Division of Hematology The Ohio State University Comprehensive Cancer Center Columbus OH Myeloma Service Memorial Sloan Kettering Cancer Center New York NY Myeloma Waldenstrom's and Amyloidosis Program Simmons Comprehensive Cancer Center UT Southwestern Medical Center Dallas TX Division of Blood and Marrow Transplant/Hematology OhioHealth Columbus OH Gibbs Cancer Center & Research Institute Spartanburg SC Alabama Oncology University of Alabama at Birmingham Birmingham AL Winship Cancer Institute of Emory University Atlanta GA Division of Hematology and Oncology Department of Internal Medicine University of Michigan Ann Arbor MI Levine Cancer Institute Atrium Health Wake Forest University School of Medicine Charlotte NC Department of Lymphoma and Myeloma The University of Texas MD Anderson Cancer Center Houston TX Division of Medical Oncology University of Washington and Fred Hutchinson Cancer Center Seattle WA Section of Hematology and Oncology Atrium Health Wake Forest Baptist Medical Center Winston-Salem NC Moores Cancer Center at University of California San Diego San Diego CA Center for Multiple Myeloma Massachusetts General Hospital Harvard Medical School Boston MA

BackgroundErythrocyte Duffy null phenotype, seen in ∼66% of African American (AA) and 0, and pts with elevated LDH. Treatment duration was longer than in ITT pts: median duration from randomization (RVd-alone vs RVd+...

BackgroundErythrocyte Duffy null phenotype, seen in ∼66% of African American (AA) and <1% of White pts, is associated with lower absolute neutrophil count (ANC) and has a key role in cytokine and chemokine homeostasis, which may influence MM pathobiology, response to proinflammatory stressors, and treatment effect. The DETERMINATION trial of RVd-alone vs RVd+ASCT in NDMM showed significantly improved progression-free survival (PFS; median 46.2 vs 67.5 mos; hazard ratio [HR] 1.53, 95% CI 1.23–1.91) with RVd+ASCT. PFS was improved with RVd+ASCT in White pts (n=540, 74.8%; median 44.3 vs 67.2 mos; HR 1.67, 95% CI 1.29–2.15), but in AA pts (n=132, 18.3%) median PFS was not reached (NR) vs 61.4 mos (HR 1.07, 95% CI 0.61–1.89). Race is an inadequate explanation for differences in outcomes; we hypothesized that Duffy null phenotype may influence outcomes and magnitude of benefit with these treatment modalities in NDMM. MethodsPts received RVd-alone or RVd+ASCT followed by R maintenance until progression. Peripheral blood samples underwent genomics analysis for SNP rs2814778 and were classified as C/C (Duffy null) or non-C/C (Duffy non-null). ResultsDuffy status is currently available for 295 pts (Fig 1). The cohort is broadly representative of the ITT population but has fewer AA pts, pts with ECOG PS >0, and pts with elevated LDH. Treatment duration was longer than in ITT pts: median duration from randomization (RVd-alone vs RVd+ASCT) was 62.2 vs 36.5 mos in Duffy null and 44.7 vs 45.5 mos in Duffy non-null pts; median duration of R maintenance was 55.2 vs 30.4 mos in Duffy null and 38.5 vs 42.9 mos in Duffy non-null pts. Median (IQR) baseline ANC was 2.8 (2.1–4.2) in Duffy null and 3.3 (2.5–4.7) x 10 9/L in Duffy non-null pts. Rates of grade ≥3 hematologic adverse events (AEs) during all treatment (RVd-alone vs RVd+ASCT) were 69.2% vs 93.8% in Duffy null and 58.7% vs 96.6% in Duffy non-null pts; rates of grade ≥3 hematologic AEs during R maintenance were 23.1% vs 57.1% in

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Nivolumab plus low-dose ipilimumab in hypermutated HER2-negative metastatic breast cancer: a phase II trial (NIMBUS)

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Nature Communications 2025年第1期16卷 1-13页

作者： Barroso-Sousa, Romualdo Zanudo, Jorge Gomez Tejeda Li, Tianyu Reddy, Sangeetha M. Emens, Leisha A. Kuntz, Thomas M. Silva, Carolina Alves Costa AlDubayan, Saud H. Chu, Hoyin Overmoyer, Beth Lange, Paulina DiLullo, Molly K. Montesion, Meagan Kasparian, Julie Hughes, Melissa E. Attaya, Victoria Basta, Ameer Lin, Nancy U. Tayob, Nabihah Jeselsohn, Rinath Mittendorf, Elizabeth A. Tolaney, Sara M. Hospital Brasília Rede Américas Brasilia Brazil Medical Oncology Dana-Farber Cancer Institute Boston MA United States Breast Oncology Program Dana-Farber Brigham Cancer Center Boston MA United States Harvard Medical School Boston MA United States Data Science Dana-Farber Cancer Institute Boston MA United States University of Texas Southwestern Medical Center Dallas TX United States University of Pittsburgh Medical Center Pittsburgh PA United States Department of Biostatistics Harvard T. H. Chan School of Public Health Boston MA United States Gustave Roussy Cancer Campus (GRCC) Clinicobiome Cedex Villejuif France Foundation Medicine Inc. Boston MA United States Division of Breast Surgery Department of Surgery Brigham and Women’s Hospital Boston MA United States

In the phase II NIMBUS trial, patients with human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer (MBC) and high tumor mutational burden (TMB ≥ 9 mut/Mb) received nivolumab (3 mg/kg biweekly) and low-dose ipilimumab (1 mg/kg every 6 weeks) for 2 years or until progression. The primary endpoint was objective response rate (ORR) per RECIST 1.1 criteria. Among 30 patients enrolled, the median TMB was 10.9 mut/Mb (range: 9–110) and the confirmed objective response rate was 20%. Secondary endpoints included progression-free survival, overall survival, clinical benefit rate, and safety and tolerability, including immune-related adverse events (irAEs). A prespecified correlative outcome was to evaluate the ORR in patients with a TMB ≥ 14 mut/Mb. Patients with TMB ≥ 14 mut/Mb (n = 6) experienced higher response rates (60% vs 12%;p = 0.041) and showed a trend towards improved progression-free survival and overall survival compared to patients with TMB < 14 mut/Mb. Exploratory genomic analyses suggested that ESR1 and PTEN mutations may be associated with poor response, while clinical benefit was associated with a decrease or no change in tumor fraction by serial circulating tumor DNA during treatment. Stool microbiome analysis revealed that baseline blood TMB, PD-L1 positivity, and immune-related diarrhea are associated with distinct taxonomic profiles. In summary, some patients with hypermutated HER2-negative MBC experience extended clinical benefit with a dual immunotherapy regimen;a higher TMB, and additional genomic and microbiome biomarkers may optimize patient selection for therapy with nivolumab plus low-dose ipilimumab. (Funded by Bristol Myers Squibb;*** identifier, NCT03789110). © The Author(s) 2025.

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*** - A plug-and-play solution for online systems medicine and network-based drug repurposing

arXiv

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arXiv 2023年

作者： Maier, Andreas Hartung, Michael Abovsky, Mark Adamowicz, Klaudia Bader, Gary D. Baier, Sylvie Blumenthal, David B. Chen, Jing Elkjaer, Maria L. Garcia-Hernandez, Carlos Helmy, Mohamed Hoffmann, Markus Jurisica, Igor Kotlyar, Max Lazareva, Olga Levi, Hagai List, Markus Lobentanzer, Sebastian Loscalzo, Joseph Malod-Dognin, Noel Manz, Quirin Matschinske, Julian Mee, Miles Oubounyt, Mhaned Pico, Alexander R. Pillich, Rudolf T. Poschenrieder, Julian M. Pratt, Dexter Pržulj, Nataša Sadegh, Sepideh Saez-Rodriguez, Julio Sarkar, Suryadipto Shaked, Gideon Shamir, Ron Trummer, Nico Turhan, Ugur Wang, Ruisheng Zolotareva, Olga Baumbach, Jan Institute for Computational Systems Biology University of Hamburg Hamburg Germany Division of Orthopaedic Surgery Schroeder Arthritis Institute Data Science Discovery Centre Osteoarthritis Research Program Krembil Research Institute UHN Toronto Canada Data Science Discovery Centre for Chronic Diseases Krembil Research Institute University Health Network 60 Leonard Avenue 5KD-407 TorontoONM5T 0S8 Canada Department of Molecular Genetics University of Toronto TorontoON Canada The Donnelly Centre University of Toronto TorontoON Canada Department of Computer Science University of Toronto TorontoON Canada Princess Margaret Cancer Centre University Health Network TorontoON Canada The Lunenfeld-Tanenbaum Research Institute Mount Sinai Hospital TorontoON Canada TUM School of Life Sciences Technical University of Munich Munich Germany Erlangen91052 Germany Department of Medicine University of California San Diego 9500 Gilman Drive La Jolla CA92093 United States Department of Neurology Odense University Hospital Odense Denmark Institute of Clinical Research University of Southern Denmark Odense Denmark Institute of Molecular Medicine University of Southern Denmark Odense Denmark Barcelona08034 Spain Institute for Advanced Study Lichtenbergstrasse 2a GarchingD-85748 Germany Technical University of Munich Germany National Institute of Diabetes Digestive and Kidney Diseases BethesdaMD20892 United States Departments of Medical Biophysics and Computer Science University of Toronto Toronto Canada Institute of Neuroimmunology Slovak Academy of Sciences Bratislava Slovakia Heidelberg69120 Germany Heidelberg Germany European Molecular Biology Laboratory Genome Biology Unit Heidelberg69117 Germany Blavatnik School of Computer Science Tel-Aviv University Tel-Aviv Israel Heidelberg University Faculty of Medicine Heidelberg University Hospital Institute for Computational Biomedicine Bioquant Heidelberg Germany Department of Medicine Bri

In recent decades, the development of new drugs has become increasingly expensive and inefficient, and the molecular mechanisms of most pharmaceuticals remain poorly understood. In response, computational systems and network medicine tools have emerged to identify potential drug repurposing candidates. However, these tools often require complex installation and lack intuitive visual network mining capabilities. To tackle these challenges, we introduce ***, a platform that assists specialized computational medicine tools in becoming user-friendly, web-based utilities for drug repurposing. With just three lines of code, *** turns any systems biology software into an interactive web tool for modeling and analyzing complex protein-drug-disease networks. Demonstrating its broad adaptability, *** has been successfully integrated with 21 computational systems medicine tools. Available at https://***, *** has significant potential for streamlining the drug discovery process, allowing researchers to focus on essential aspects of pharmaceutical treatment research. © 2023, CC BY.

关键词： data visualization

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Improved Risk Stratification of Smoldering Multiple Myeloma (SMM) Using Trajectory data in the Pangea 2.0 Model: A Multicenter Study in 1,431 Participants

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Blood 2024年 144卷 1017-1017页

作者： Floris Chabrun Daniel Schwartz Susanna Gentile Tulika R Gupta Noelia Collado Gisbert Esperanza Martín-Sánchez Rosalinda Termini Jacqueline F Perry Annie Cowan Federico Ferrari Samuel Freeman Robert A. Redd Vidhi Patel Patrick Costello Catherine Tobia Romanos Sklavenitis-Pistofidis Habib El-Khoury Michael Timonian David J Lee Elizabeth D. Lightbody Irene Ghobrial Dana-Farber Cancer Institute Boston MA Harvard T.H. Chan School of Public Health Boston MA Cancer Center Clinica Universidad de Navarra (CCUN) Centro de Investigacion Medica Aplicada (CIMA) Instituto de Investigacion Sanitaria de Navarra (IdiSNA) CIBER-ONC numbers CB16/12/00369 and CB16/12/00489 Pamplona Spain Biostatistics and Research Decision Sciences Merck & Co Rahway NJ Bioinformatics Program Broad Institute of MIT and Harvard Cambridge MA Department of Data Science Dana-Farber Cancer Institute Boston MA Broad Institute of MIT and Harvard Cambridge MA University of Chicago Medical Center Chicago IL Harvard Medical School Boston MA

Background The 20/2/20 model is the current gold standard to stratify smoldering multiple myeloma (SMM) patients at baseline into three subgroups (low, intermediate, and high) according to the risk of progression based on the free light chain ratio (FLCr), M-protein concentration, and percentage of bone marrow (BM) plasma cells (PC). Evolving patterns that may alter the risk of progression are not considered in this static model. We previously proposed the PANGEA model that allows for personalized risk prediction using FLCr, M-protein, creatinine, age, hemoglobin trajectory, and optionally BM PC. We developed an improved PANGEA 2.0 model that includes trajectory modeling of these biomarkers to capture evolving patterns and improve predictions of MM progression. Methods We conducted a retrospective review of clinical data from 1,431 participants diagnosed with SMM at 4 international sites (Dana-Farber cancer Institute, Boston, US, n = 737; National and Kapodistrian University of Athens, Greece, n = 379; University College London, UK, n = 97; and University of Navarra, Spain, n = 218). Dana-Farber participants comprised a training cohort to identify biomarker trajectories and to develop the PANGEA 2.0 model. The model was validated on two international cohorts: validation cohort 1 included patients from Greece and the UK (n = 476) and validation cohort 2 included patients from Spain (n = 218). The longitudinal data collected from 2018-2024 included current values and historical trajectories of age, M-protein, FLCr, creatinine, and hemoglobin, as well as BM PC (optional). We used a systematic grid search with 5-fold cross-validation to determine optimal trajectory definitions for M-protein, FLCr, creatinine, and hemoglobin. For each, we evaluated seven binary trajectory definitions based on average increase over time (slopes) or recent increase from the previous visit on absolute or relative (%) increase scales, with varying thresholds and time periods. We used Cox reg

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