1
|
Fischer SN, Claussen ER, Kourtis S, Sdelci S, Orchard S, Hermjakob H, Kustatscher G, Drew K. hu.MAP3.0: atlas of human protein complexes by integration of >25,000 proteomic experiments. Mol Syst Biol 2025:10.1038/s44320-025-00121-5. [PMID: 40425816 DOI: 10.1038/s44320-025-00121-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2024] [Revised: 05/07/2025] [Accepted: 05/09/2025] [Indexed: 05/29/2025] Open
Abstract
Macromolecular protein complexes carry out most cellular functions. Unfortunately, we lack the subunit composition for many human protein complexes. To address this gap we integrated >25,000 mass spectrometry experiments using a machine learning approach to identify >15,000 human protein complexes. We show our map of protein complexes is highly accurate and more comprehensive than previous maps, placing nearly 70% of human proteins into their physical contexts. We globally characterize our complexes using mass spectrometry based protein covariation data (ProteomeHD.2) and identify covarying complexes suggesting common functional associations. hu.MAP3.0 generates testable functional hypotheses for 472 uncharacterized proteins which we support using AlphaFold modeling. Additionally, we use AlphaFold modeling to identify 5871 mutually exclusive proteins in hu.MAP3.0 complexes suggesting complexes serve different functional roles depending on their subunit composition. We identify expression as the primary way cells and organisms relieve the conflict of mutually exclusive subunits. Finally, we import our complexes to EMBL-EBI's Complex Portal ( https://www.ebi.ac.uk/complexportal/home ) and provide complexes through our hu.MAP3.0 web interface ( https://humap3.proteincomplexes.org/ ). We expect our resource to be highly impactful to the broader research community.
Collapse
Affiliation(s)
- Samantha N Fischer
- Department of Biological Sciences, University of Illinois at Chicago, Chicago, IL, 60607, USA
| | - Erin R Claussen
- Department of Biological Sciences, University of Illinois at Chicago, Chicago, IL, 60607, USA
| | - Savvas Kourtis
- Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Barcelona, Spain
| | - Sara Sdelci
- Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Barcelona, Spain
| | - Sandra Orchard
- European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI), Wellcome Genome Campus, Hinxton, Cambridge, CB10 1SD, UK
| | - Henning Hermjakob
- European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI), Wellcome Genome Campus, Hinxton, Cambridge, CB10 1SD, UK
| | - Georg Kustatscher
- Centre for Cell Biology, University of Edinburgh, Edinburgh, EH9 3BF, UK
| | - Kevin Drew
- Department of Biological Sciences, University of Illinois at Chicago, Chicago, IL, 60607, USA.
| |
Collapse
|
2
|
Xia J, Zheng L, Zhang H, Fan Q, Liu H, Wang O, Yan H. Drug Resistance Analysis of Pancreatic Cancer Based on Universally Differentially Expressed Genes. Int J Mol Sci 2025; 26:3936. [PMID: 40362181 PMCID: PMC12071644 DOI: 10.3390/ijms26093936] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2025] [Revised: 04/10/2025] [Accepted: 04/11/2025] [Indexed: 05/15/2025] Open
Abstract
The high heterogeneity between patients can complicate the diagnosis and treatment of pancreatic ductal adenocarcinoma (PDAC). Here, we explored the association of universally differentially expressed genes (UDEGs) with resistance to chemotherapy and immunotherapy in the context of pancreatic cancer. In this work, sixteen up-regulated and three down-regulated genes that were dysregulated in more than 85% of 102 paired and 5% of 521 unpaired PDAC samples were identified and defined as UDEGs. A single-cell level analysis further validated the high expression levels of the up-UDEGs and the low levels of the down-UDEGs in cancer-related ductal cells, which could represent the malignant changes seen in pancreatic cancer. Based on a drug sensitivity analysis, we found that ANLN, GPRC5A and SERPINB5 are closely related to the resistance mechanism of PDAC, and their high expression predicted worse survival for PDAC patients. This suggests that targeting these genes could be a potential way to reduce drug resistance and improve survival. Based on the immune infiltration analysis, the abnormal expression of the UDEGs was found to be related to the formation of an immunosuppressive tumor microenvironment. In conclusion, these UDEGs are common features of PDAC and could be involved in the resistance of pancreatic cancer and might serve as novel drug targets to guide research into drug repurposing.
Collapse
Affiliation(s)
- Jie Xia
- School of Biology and Engineering, Guizhou Medical University, Guiyang 550025, China;
- Fujian Key Laboratory of Medical Bioinformatics, Department of Bioinformatics, School of Medical Technology and Engineering, Fujian Medical University, Fuzhou 350100, China; (L.Z.); (H.Z.); (Q.F.); (H.L.); (O.W.)
| | - Linyong Zheng
- Fujian Key Laboratory of Medical Bioinformatics, Department of Bioinformatics, School of Medical Technology and Engineering, Fujian Medical University, Fuzhou 350100, China; (L.Z.); (H.Z.); (Q.F.); (H.L.); (O.W.)
| | - Huarong Zhang
- Fujian Key Laboratory of Medical Bioinformatics, Department of Bioinformatics, School of Medical Technology and Engineering, Fujian Medical University, Fuzhou 350100, China; (L.Z.); (H.Z.); (Q.F.); (H.L.); (O.W.)
| | - Qi Fan
- Fujian Key Laboratory of Medical Bioinformatics, Department of Bioinformatics, School of Medical Technology and Engineering, Fujian Medical University, Fuzhou 350100, China; (L.Z.); (H.Z.); (Q.F.); (H.L.); (O.W.)
| | - Hui Liu
- Fujian Key Laboratory of Medical Bioinformatics, Department of Bioinformatics, School of Medical Technology and Engineering, Fujian Medical University, Fuzhou 350100, China; (L.Z.); (H.Z.); (Q.F.); (H.L.); (O.W.)
| | - Ouxi Wang
- Fujian Key Laboratory of Medical Bioinformatics, Department of Bioinformatics, School of Medical Technology and Engineering, Fujian Medical University, Fuzhou 350100, China; (L.Z.); (H.Z.); (Q.F.); (H.L.); (O.W.)
| | - Haidan Yan
- Fujian Key Laboratory of Medical Bioinformatics, Department of Bioinformatics, School of Medical Technology and Engineering, Fujian Medical University, Fuzhou 350100, China; (L.Z.); (H.Z.); (Q.F.); (H.L.); (O.W.)
| |
Collapse
|
3
|
Espinoza-Ferrao S, Echeverría-Garcés G, Rivera-Orellana S, Bueno-Miño J, Castellanos-Molina E, Benítez-Núñez M, López-Cortés A. Global analysis of actionable genomic alterations in thyroid cancer and precision-based pharmacogenomic strategies. Front Pharmacol 2025; 16:1524623. [PMID: 40297138 PMCID: PMC12034932 DOI: 10.3389/fphar.2025.1524623] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2024] [Accepted: 04/01/2025] [Indexed: 04/30/2025] Open
Abstract
Introduction Thyroid cancer, a prevalent endocrine malignancy, has an age-standardized incidence rate of 9.1 per 100,000 people and a mortality rate of 0.44 per 100,000 as of 2024. Despite significant advances in precision oncology driven by large-scale international consortia, gaps persist in understanding the genomic landscape of thyroid cancer and its impact on therapeutic efficacy across diverse populations. Methods To address this gap, we performed comprehensive data mining and in silico analyses to identify pathogenic variants in thyroid cancer driver genes, calculate allele frequencies, and assess deleteriousness scores across global populations, including African, Amish, Ashkenazi Jewish, East and South Asian, Finnish and non-Finnish European, Latino, and Middle Eastern groups. Additionally, pharmacogenomic profiling, in silico drug prescription, and clinical trial data were analyzed to prioritize targeted therapeutic strategies. Results Our analysis examined 56,622 variants in 40 thyroid cancer-driver genes across 76,156 human genomes, identifying 5,001 known and predicted oncogenic variants. Enrichment analysis revealed critical pathways such as MAPK, PI3K-AKT-mTOR, and p53 signaling, underscoring their roles in thyroid cancer pathogenesis. High-throughput validation strategies confirmed actionable genomic alterations in RET, BRAF, NRAS, KRAS, and EPHA7. Ligandability assessments identified these proteins as promising therapeutic targets. Furthermore, our findings highlight the clinical potential of targeted drug inhibitors, including vandetanib, dabrafenib, and selumetinib, for improving treatment outcomes. Discussion This study underscores the significance of integrating genomic insights with pharmacogenomic strategies to address disparities in thyroid cancer treatment. The identification of population-specific oncogenic variants and actionable therapeutic targets provides a foundation for advancing precision oncology. Future efforts should focus on including underrepresented populations, developing population-specific prevention strategies, and fostering global collaboration to ensure equitable access to pharmacogenomic testing and innovative therapies. These initiatives have the potential to transform thyroid cancer care and align with the broader goals of personalized medicine.
Collapse
Affiliation(s)
| | - Gabriela Echeverría-Garcés
- Centro de Referencia Nacional de Genómica, Secuenciación y Bioinformática, Instituto Nacional de Investigación en Salud Pública “Leopoldo Izquieta Pérez”, Quito, Ecuador
- Latin American Network for the Implementation and Validation of Clinical Pharmacogenomics Guidelines (RELIVAF-CYTED), Santiago, Chile
| | | | - José Bueno-Miño
- Cancer Research Group (CRG), Faculty of Medicine, Universidad de Las Américas, Quito, Ecuador
| | | | - Melanie Benítez-Núñez
- Cancer Research Group (CRG), Faculty of Medicine, Universidad de Las Américas, Quito, Ecuador
| | - Andrés López-Cortés
- Cancer Research Group (CRG), Faculty of Medicine, Universidad de Las Américas, Quito, Ecuador
| |
Collapse
|
4
|
De la Cruz-Cano E, González-Díaz JÁ, Olivares-Corichi IM, Ayala-Sumuano JT, Díaz-Gandarilla JA, Torres-Sauret Q, Larios-Serrato V, Vilchis-Reyes MÁ, López-Victorio CJ, González-Garrido JA, García-Sánchez JR. Identifying Genes Associated with the Anticancer Activity of a Fluorinated Chalcone in Triple-Negative Breast Cancer Cells Using Bioinformatics Tools. Int J Mol Sci 2025; 26:3662. [PMID: 40332279 PMCID: PMC12027753 DOI: 10.3390/ijms26083662] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2025] [Revised: 04/04/2025] [Accepted: 04/08/2025] [Indexed: 05/08/2025] Open
Abstract
Fluorinated chalcones are molecules reported to possess potent anticancer properties against triple-negative breast cancer (TNBC) cells. However, their molecular mechanisms have not yet been fully explored. Using bioinformatics tools, we analyzed the transcriptomes of MDA-MB-231 cells treated with either a novel fluorinated chalcone (compound 3) or a control in order to identify differentially expressed (DE) genes associated with its anticancer activity and determine the biological processes in which these genes are involved. A fluorinated chalcone was synthesized using the Claisen-Schmidt method. The transcriptome of MDA-MB-231 cells was then analyzed on an Illumina NextSeq500, and DE genes with significant changes in expression were identified using the DESeq2 v1.38.0 bioinformatics tool under the strict detection criteria of |log2FC| ≥ 2 and adjusted p < 0.05. We identified 504 DE genes, which were enriched in terms related to "regulation of cell death", "cation transport", "response to topologically incorrect proteins", and "response to unfolded proteins". Surprisingly, these genes were involved in "the HSF1-dependent transactivation pathway" and "the attenuation phase pathway". This bioinformatics-based study suggests that the tested fluorinated chalcone could influence HSF-1 silencing in addition to promoting the up-regulation of several genes involved in stress-induced apoptosis. Therefore, the tested compound could have enormous potential as a novel approach for TNBC treatment.
Collapse
Affiliation(s)
- Eduardo De la Cruz-Cano
- Laboratorio de Bioquímica y Biología Molecular, División Académica de Ciencias Básicas, Centro de Investigación de Ciencia y Tecnología Aplicada de Tabasco (CICTAT), Universidad Juárez Autónoma de Tabasco, Cunduacán C.P. 86690, Mexico; (E.D.l.C.-C.); (J.Á.G.-D.); (Q.T.-S.); (M.Á.V.-R.); (J.A.G.-G.)
| | - José Ángel González-Díaz
- Laboratorio de Bioquímica y Biología Molecular, División Académica de Ciencias Básicas, Centro de Investigación de Ciencia y Tecnología Aplicada de Tabasco (CICTAT), Universidad Juárez Autónoma de Tabasco, Cunduacán C.P. 86690, Mexico; (E.D.l.C.-C.); (J.Á.G.-D.); (Q.T.-S.); (M.Á.V.-R.); (J.A.G.-G.)
| | - Ivonne María Olivares-Corichi
- Laboratorio de Oncología Molecular y Estrés Oxidativo, Escuela Superior de Medicina, Instituto Politécnico Nacional, Ciudad de México C.P. 11340, Mexico;
| | | | - José Alfredo Díaz-Gandarilla
- Laboratorio de Análisis Clínicos, División Académica Multidisciplinaria de Comalcalco, Universidad Juárez Autónoma de Tabasco, Comalcalco C.P. 86650, Mexico;
| | - Quirino Torres-Sauret
- Laboratorio de Bioquímica y Biología Molecular, División Académica de Ciencias Básicas, Centro de Investigación de Ciencia y Tecnología Aplicada de Tabasco (CICTAT), Universidad Juárez Autónoma de Tabasco, Cunduacán C.P. 86690, Mexico; (E.D.l.C.-C.); (J.Á.G.-D.); (Q.T.-S.); (M.Á.V.-R.); (J.A.G.-G.)
| | - Violeta Larios-Serrato
- Laboratorio de Biotecnología Genómica y Bioinformática, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, Ciudad de México C.P. 11340, Mexico;
| | - Miguel Ángel Vilchis-Reyes
- Laboratorio de Bioquímica y Biología Molecular, División Académica de Ciencias Básicas, Centro de Investigación de Ciencia y Tecnología Aplicada de Tabasco (CICTAT), Universidad Juárez Autónoma de Tabasco, Cunduacán C.P. 86690, Mexico; (E.D.l.C.-C.); (J.Á.G.-D.); (Q.T.-S.); (M.Á.V.-R.); (J.A.G.-G.)
| | - Carlos Javier López-Victorio
- Laboratorio de Bioquímica y Biología Molecular, División Académica de Ciencias Básicas, Centro de Investigación de Ciencia y Tecnología Aplicada de Tabasco (CICTAT), Universidad Juárez Autónoma de Tabasco, Cunduacán C.P. 86690, Mexico; (E.D.l.C.-C.); (J.Á.G.-D.); (Q.T.-S.); (M.Á.V.-R.); (J.A.G.-G.)
| | - José Arnold González-Garrido
- Laboratorio de Bioquímica y Biología Molecular, División Académica de Ciencias Básicas, Centro de Investigación de Ciencia y Tecnología Aplicada de Tabasco (CICTAT), Universidad Juárez Autónoma de Tabasco, Cunduacán C.P. 86690, Mexico; (E.D.l.C.-C.); (J.Á.G.-D.); (Q.T.-S.); (M.Á.V.-R.); (J.A.G.-G.)
| | - José Rubén García-Sánchez
- Laboratorio de Oncología Molecular y Estrés Oxidativo, Escuela Superior de Medicina, Instituto Politécnico Nacional, Ciudad de México C.P. 11340, Mexico;
| |
Collapse
|
5
|
Madhawa K, Svensson T, Nt H, Chung UI, Svensson AK. Associations between plasma proteomic signatures and secondary sleep in older adults. GeroScience 2025:10.1007/s11357-025-01565-1. [PMID: 40198463 DOI: 10.1007/s11357-025-01565-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2024] [Accepted: 02/10/2025] [Indexed: 04/10/2025] Open
Abstract
Sleep disturbances are prevalent among elderly populations and are linked to various health complications. Understanding the underlying biological mechanisms contributing to sleep disorders is crucial for developing targeted interventions. In this study, we measured 355 plasma proteins in an elderly Japanese cohort (n=77) using a high-throughput proteomic platform. Additionally, we collected over 25,000 person-days of physical activity and sleep behavior data from wrist-worn wearable devices, focusing on total sleep time (TST) across 24 h and daytime sleep. Fragmented sleep was observed as one of the most prevalent sleep disturbances in this population. In protein expression analysis, we identified 9 protein biomarkers associated with increased secondary sleep TST, defined as additional sleep episodes outside of the main sleep episode within 24 h. These findings may suggest disruptions in circadian rhythms or underlying health conditions. Functional analysis revealed that biological processes related to inflammation play a significant role in regulating sleep behavior. Further analysis showed an association of 12 proteins with daytime sleep and 5 proteins with afternoon sleep. Overall, this study identified inflammatory biomarkers and biological processes associated with sleep behavior in the elderly, presenting promising opportunities for developing diagnostic tools and targeted clinical interventions.
Collapse
Affiliation(s)
- Kaushalya Madhawa
- Precision Health, Department of Bioengineering, Graduate School of Engineering, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8656, Japan
| | - Thomas Svensson
- Precision Health, Department of Bioengineering, Graduate School of Engineering, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8656, Japan.
- Graduate School of Health Innovation, Kanagawa University of Human Services, Kawasaki-ku, Kawasaki-shi, Kanagawa, 210-0821, Japan.
- Department of Clinical Sciences, Lund University, Skåne University Hospital, Malmö, Sweden.
| | - Hoang Nt
- Precision Health, Department of Bioengineering, Graduate School of Engineering, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8656, Japan
| | - Ung-Il Chung
- Precision Health, Department of Bioengineering, Graduate School of Engineering, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8656, Japan
- Graduate School of Health Innovation, Kanagawa University of Human Services, Kawasaki-ku, Kawasaki-shi, Kanagawa, 210-0821, Japan
- Clinical Biotechnology, Center for Disease Biology and Integrative Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Akiko Kishi Svensson
- Precision Health, Department of Bioengineering, Graduate School of Engineering, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8656, Japan
- Department of Clinical Sciences, Lund University, Skåne University Hospital, Malmö, Sweden
- Department of Diabetes and Metabolic Diseases, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan
| |
Collapse
|
6
|
Doerfler P, Schoefmann N, Cabral G, Bauer W, Berli MC, Binder B, Borst C, Botter S, French LE, Goerge T, Hafner J, Hartmann D, Høgh A, Hoetzenecker W, Holzer-Geissler JCJ, Kamolz LP, Kofler K, Luger T, Nischwitz SP, Popovits M, Rappersberger K, Restivo G, Schlager JG, Schmuth M, Stingl G, Stockinger T, Stroelin A, Stuetz A, Umlauft J, Weninger WP, Wolff-Winiski B. Development of a Cellular Assay as a Personalized Model for Testing Chronic Wound Therapeutics. J Invest Dermatol 2025; 145:631-644.e22. [PMID: 38960086 DOI: 10.1016/j.jid.2024.05.029] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2023] [Revised: 03/19/2024] [Accepted: 05/01/2024] [Indexed: 07/05/2024]
Abstract
Exudates of nonhealing wounds contain drivers of pathogenicity. We utilized >800 exudates from nonhealing and healing wounds of diverse etiologies, collected by 3 different methods, to develop a wound-specific, cell-based functional biomarker assay. Human dermal fibroblast proliferation served as readout to (i) differentiate between healing and nonhealing wounds, (ii) follow the healing process of individual patients, and (iii) assess the effects of therapeutics for chronic wounds ex vivo. We observed a strong correlation between wound chronicity and inhibitory effects of individual exudates on fibroblast proliferation, with good diagnostic sensitivity (76-90%, depending on the sample collection method). Transition of a clinically nonhealing to a healing phenotype restored fibroblast proliferation and extracellular matrix formation while reducing inflammatory cytokine production. Transcriptional analysis of fibroblasts exposed to ex vivo nonhealing wound exudates revealed an induction of inflammatory cytokine and chemokine pathways and the unfolded protein response, indicating that these changes may contribute to the pathology of nonhealing wounds. Testing the wound therapeutics, PDGF and silver sulfadiazine, yielded responses in line with clinical experience and indicates the usefulness of the assay to search for and profile new therapeutics.
Collapse
Affiliation(s)
| | | | | | - Wolfgang Bauer
- Department of Dermatology, Medical University of Vienna, Vienna, Austria
| | - Martin C Berli
- Balgrist University Hospital, Zurich, Switzerland; Technical Orthopedics, Diabetic Foot Consultation, Wound Outpatient Clinic, Spital Limmattal, Schlieren, Switzerland
| | - Barbara Binder
- Department of Dermatology and Venerology, Medical University of Graz, Graz, Austria
| | - Carina Borst
- Department of Dermatology, Medical University of Vienna, Vienna, Austria
| | - Sander Botter
- Swiss Center for Musculoskeletal Biobanking, Balgrist Campus AG, Zurich, Switzerland
| | - Lars E French
- Department of Dermatology and Allergology, University Hospital, Ludwig-Maximilians-University Munich, Munich, Germany
| | - Tobias Goerge
- Department of Dermatology, University of Münster, Muenster, Germany
| | - Juerg Hafner
- Department of Dermatology, University Hospital of Zurich, Zurich, Switzerland
| | - Daniela Hartmann
- Department of Dermatology and Allergology, University Hospital, Ludwig-Maximilians-University Munich, Munich, Germany
| | - Annette Høgh
- Department of Vascular Surgery, Regionshospitalet Viborg, Viborg, Denmark
| | | | - Judith C J Holzer-Geissler
- Division of Plastic, Aesthetic and Reconstructive Surgery, Department of Surgery, Medical University of Graz, Graz, Austria
| | - Lars P Kamolz
- Division of Plastic, Aesthetic and Reconstructive Surgery, Department of Surgery, Medical University of Graz, Graz, Austria
| | - Katrin Kofler
- Department of Dermatology, Medical University of Tübingen, Tuebingen, Germany
| | - Thomas Luger
- Department of Dermatology, University of Münster, Muenster, Germany
| | - Sebastian P Nischwitz
- Division of Plastic, Aesthetic and Reconstructive Surgery, Department of Surgery, Medical University of Graz, Graz, Austria
| | - Michael Popovits
- Department of Surgery, Barmherzige Brueder Hospital Graz, Graz, Austria; Privatklinik Graz Ragnitz, Graz, Austria
| | | | - Gaetana Restivo
- Department of Dermatology, University Hospital of Zurich, Zurich, Switzerland
| | - Justin G Schlager
- Department of Dermatology and Allergology, University Hospital, Ludwig-Maximilians-University Munich, Munich, Germany
| | - Matthias Schmuth
- Department of Dermatology, Venerology and Allergology, Medical University of Innsbruck, Innsbruck, Austria
| | - Georg Stingl
- Department of Dermatology, Medical University of Vienna, Vienna, Austria
| | | | - Anke Stroelin
- Department of Dermatology, Medical University of Tübingen, Tuebingen, Germany
| | | | - Julian Umlauft
- Department of Dermatology, Venerology and Allergology, Medical University of Innsbruck, Innsbruck, Austria; Dermatology, Zellmed Medalp, Zell am Ziller, Austria
| | | | | |
Collapse
|
7
|
Su Y, Feng C, Ye W, Xiao J, Meng Q, Yang X, Wang Y, Huang T, Lan L, Chen S, Ding Z, Su S, Wei S, Shan Q. Exploring the dynamic responses of group 3 innate lymphoid cells at different times in response to LPS challenge. Int Immunopharmacol 2025; 148:114162. [PMID: 39889415 DOI: 10.1016/j.intimp.2025.114162] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2024] [Revised: 01/12/2025] [Accepted: 01/22/2025] [Indexed: 02/03/2025]
Abstract
Group 3 innate lymphoid cells (ILC3s) have clear roles in regulating mucosal immunity and tissue homeostasis in the intestine, though the immunological functions in lungs remain unclear. This study aimed to demonstrate the dynamic responses of ILC3s to acute inflammation upon LPS challenge. Microarray data and single-cell RNA sequencing (scRNA-seq) data obtained from the GEO database were combined to analyze the function of ILC3 subset, confirmed by flow cytometry assay and qRT-PCR. The gene enrichment analysis of intersected genes identified between microarray data in bacterial pneumonia and single-cell RNA sequencing of intestinal ILC3s were closely related to TNF-alpha effects on cytokine activity, cell motility and apoptosis pathway, indicating the possibility of intestinal ILC3s migration to the lung. Furthermore, the cellular landscapes of ILC3s in lung and intestine at different times after pulmonary infection exhibited varied ILC3 statuses. ILC3s in lung expanded a lot at 48 h while intestinal ILC3s decreased at 72 h response to LPS challenge, with higher expression of marked genes related to TNF-alpha effects on cytokine activity, cell motility and apoptosis pathway. The main findings in our study may serve as valuable resources for understanding the roles that ILC3s play upon LPS challenge, which may offer opportunities for translating ILC3s as therapeutic targets to regulate LPS-induced pulmonary inflammation.
Collapse
Affiliation(s)
- Ying Su
- Department of Pediatrics The First Affiliated Hospital of Guangxi Medical University/Difficult and Critical Illness Center Pediatric Clinical Medical Research Center of Guangxi Nanning China
| | - Caixia Feng
- Department of Pediatrics The First Affiliated Hospital of Guangxi Medical University/Difficult and Critical Illness Center Pediatric Clinical Medical Research Center of Guangxi Nanning China
| | - Wenyu Ye
- Department of Pediatrics The First Affiliated Hospital of Guangxi Medical University/Difficult and Critical Illness Center Pediatric Clinical Medical Research Center of Guangxi Nanning China
| | - Juan Xiao
- Department of Pediatrics The First Affiliated Hospital of Guangxi Medical University/Difficult and Critical Illness Center Pediatric Clinical Medical Research Center of Guangxi Nanning China
| | - Qi Meng
- Department of Pediatrics The First Affiliated Hospital of Guangxi Medical University/Difficult and Critical Illness Center Pediatric Clinical Medical Research Center of Guangxi Nanning China
| | - Xia Yang
- Department of Pediatrics The First Affiliated Hospital of Guangxi Medical University/Difficult and Critical Illness Center Pediatric Clinical Medical Research Center of Guangxi Nanning China
| | - Yongcai Wang
- Department of Pediatrics The First Affiliated Hospital of Guangxi Medical University/Difficult and Critical Illness Center Pediatric Clinical Medical Research Center of Guangxi Nanning China
| | - Ting Huang
- Guangxi Key Laboratory of Aquatic Genetic Breeding and Healthy Aquaculture Guangxi Academy of Fishery Sciences Nanning China
| | - Liancheng Lan
- Department of Pediatrics The First Affiliated Hospital of Guangxi Medical University/Difficult and Critical Illness Center Pediatric Clinical Medical Research Center of Guangxi Nanning China
| | - Sixing Chen
- Department of Pediatrics The First Affiliated Hospital of Guangxi Medical University/Difficult and Critical Illness Center Pediatric Clinical Medical Research Center of Guangxi Nanning China
| | - Ziting Ding
- Department of Pediatrics The First Affiliated Hospital of Guangxi Medical University/Difficult and Critical Illness Center Pediatric Clinical Medical Research Center of Guangxi Nanning China
| | - Shiqi Su
- Department of Pediatrics The First Affiliated Hospital of Guangxi Medical University/Difficult and Critical Illness Center Pediatric Clinical Medical Research Center of Guangxi Nanning China
| | - Sumei Wei
- Department of Pediatrics The First Affiliated Hospital of Guangxi Medical University/Difficult and Critical Illness Center Pediatric Clinical Medical Research Center of Guangxi Nanning China
| | - Qingwen Shan
- Department of Pediatrics The First Affiliated Hospital of Guangxi Medical University/Difficult and Critical Illness Center Pediatric Clinical Medical Research Center of Guangxi Nanning China.
| |
Collapse
|
8
|
Motelow JE, Malakar A, Murthy SBK, Verbitsky M, Kahn A, Estrella E, Kunkel L, Wiesenhahn M, Becket J, Harris N, Lee R, Adam R, Kiryluk K, Gharavi AG, Brownstein CA. Interstitial Cystitis: a phenotype and rare variant exome sequencing study: Interstitial Cystitis: a phenotype and exome sequencing study. MEDRXIV : THE PREPRINT SERVER FOR HEALTH SCIENCES 2025:2025.02.16.25322147. [PMID: 40034785 PMCID: PMC11875234 DOI: 10.1101/2025.02.16.25322147] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 03/05/2025]
Abstract
Interstitial cystitis/bladder pain syndrome (IC/BPS) is a poorly understood and underdiagnosed syndrome of chronic bladder/pelvic pain with urinary frequency and urgency. Though IC/BPS can be hereditary, little is known of its genetic etiology. Using the eMERGE data, we confirmed known phenotypic associations such as gastroesophageal reflux disease and irritable bowel syndrome and detected new associations, including osteoarthrosis/osteoarthritis and Barrett's esophagus. An exome wide ultra-rare variants analysis in 348 IC/BPS and 11,981 controls extended the previously reported association with ATP2C1 and ATP2A2, implicated in Mendelian desquamating skin disorders, but did not provide evidence for other previously proposed pathogenic pathways such as bladder development, nociception or inflammation. Pathway analysis detected new associations with "anaphase-promoting complex-dependent catabolic process", the "regulation of MAPK cascade" and "integrin binding". These findings suggest perturbations in biological networks for epithelial integrity and cell cycle progression in IC/BPS pathogenesis, and provide a roadmap for its future investigation.
Collapse
Affiliation(s)
- Joshua E Motelow
- Division of Critical Care and Hospital Medicine, Department of Pediatrics, Vagelos College of Physicians & Surgeons, Columbia University, New York, NY
| | - Ayan Malakar
- Division of Nephrology, Department of Medicine, Vagelos College of Physicians & Surgeons, Columbia University, New York, NY
- Center for Precision Medicine and Genomics, Department of Medicine, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY
| | - Sarath Babu Krishna Murthy
- Division of Nephrology, Department of Medicine, Vagelos College of Physicians & Surgeons, Columbia University, New York, NY
- Center for Precision Medicine and Genomics, Department of Medicine, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY
| | - Miguel Verbitsky
- Division of Nephrology, Department of Medicine, Vagelos College of Physicians & Surgeons, Columbia University, New York, NY
- Center for Precision Medicine and Genomics, Department of Medicine, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY
| | - Atlas Kahn
- Division of Nephrology, Department of Medicine, Vagelos College of Physicians & Surgeons, Columbia University, New York, NY
| | - Elicia Estrella
- Division of Genetics and Genomics, Boston Children's Hospital, Boston, MA
| | - Louis Kunkel
- Division of Genetics and Genomics, Boston Children's Hospital, Boston, MA
- The Manton Center for Orphan Disease Research, Boston Children's Hospital, Harvard Medical School, Boston MA
| | - Madelyn Wiesenhahn
- Division of Genetics and Genomics, Boston Children's Hospital, Boston, MA
- The Manton Center for Orphan Disease Research, Boston Children's Hospital, Harvard Medical School, Boston MA
| | - Jaimee Becket
- Division of Nephrology, Department of Medicine, Vagelos College of Physicians & Surgeons, Columbia University, New York, NY
- Center for Precision Medicine and Genomics, Department of Medicine, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY
| | - Natasha Harris
- Division of Nephrology, Department of Medicine, Vagelos College of Physicians & Surgeons, Columbia University, New York, NY
- Center for Precision Medicine and Genomics, Department of Medicine, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY
| | - Richard Lee
- Department of Urology, Boston Children's Hospital, Harvard Medical School, Boston MA
| | - Rosalyn Adam
- Department of Urology, Boston Children's Hospital, Harvard Medical School, Boston MA
- Department of Surgery, Harvard Medical School, Boston, MA
| | - Krzysztof Kiryluk
- Division of Nephrology, Department of Medicine, Vagelos College of Physicians & Surgeons, Columbia University, New York, NY
| | - Ali G Gharavi
- Division of Nephrology, Department of Medicine, Vagelos College of Physicians & Surgeons, Columbia University, New York, NY
- Center for Precision Medicine and Genomics, Department of Medicine, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY
| | - Catherine A Brownstein
- Division of Genetics and Genomics, Boston Children's Hospital, Boston, MA
- The Manton Center for Orphan Disease Research, Boston Children's Hospital, Harvard Medical School, Boston MA
| |
Collapse
|
9
|
Song B, Ning X, Guo L, Liu W, Jin H. Comparative Proteomics Analysis Reveals Distinct Molecular Phenotype and Biomarkers in Patients with Erythrodermic Atopic Dermatitis and Erythrodermic Psoriasis. Inflammation 2025; 48:331-345. [PMID: 38877357 DOI: 10.1007/s10753-024-02078-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2024] [Revised: 06/03/2024] [Accepted: 06/03/2024] [Indexed: 06/16/2024]
Abstract
Erythrodermic atopic dermatitis (EAD) and erythrodermic psoriasis (EP) are rare yet debilitating inflammatory skin disorders that propose challenges in diagnosis and discovering effective therapeutic targets. Despite their clinical and histological similarities, the underlying molecular mechanisms and systemic biomarkers of these diseases are substantially unclear. In this study, we sought to investigate the differential serum proteome of EP and EAD patients and identify biomarkers for these two subtypes of erythroderma. We recruited 14 EAD patients, 14 EP patients and 14 healthy controls. Serum samples were collected and analyzed using the Olink high-throughput platform to assess the levels of 269 inflammation-/immune response-/cardiovascular-related biomarkers. Both EAD and EP patients exhibited enhanced immune activation and dysregulated cardiovascular profiles compared to healthy controls. EAD demonstrated a more pronounced inflammation tone, characterized by Th1/Th2/Th22/IL-1-dominant patterns, as well as increased TNF superfamily, Th17, and apoptosis markers. Conversely, EP displayed inflammation with Th1/Th17/TNF-skewing and mild Th2 upregulation, along with notable increases in epidermal-development markers. Disease severity in EAD was strongly correlated with apoptosis/Th2 markers, while correlated with Th17 markers in EP. Furthermore, a panel of eight markers (IL-17A/IL-17C/PI3/CCL20/SH2D1A/SIRT2/DFFA/IL-13) was identified that effectively discriminated between EP and EAD, with an Area Under the Curve greater than 0.8. Our study comprehensively characterizes the circulating molecular profiles in EAD and EP patients, providing insights into the similarities and complexities of their inflammation phenotypes. The identified serum biomarkers have the potential to differentiate between EP and EAD, which could aid in the diagnosis and guiding tailored therapeutics.
Collapse
Affiliation(s)
- Biao Song
- Department of Dermatology, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China
- State Key Laboratory for Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Beijing, 100730, China
- National Clinical Research Center for Dermatologic and Immunologic Diseases, Beijing, China
| | - Xin Ning
- Department of Dermatology, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China
- State Key Laboratory for Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Beijing, 100730, China
- National Clinical Research Center for Dermatologic and Immunologic Diseases, Beijing, China
| | - Lan Guo
- Department of Dermatology, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China
- State Key Laboratory for Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Beijing, 100730, China
- National Clinical Research Center for Dermatologic and Immunologic Diseases, Beijing, China
| | - Weida Liu
- State Key Laboratory for Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Beijing, 100730, China
- Medical Research Center, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, 100730, China
| | - Hongzhong Jin
- Department of Dermatology, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China.
- State Key Laboratory for Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Beijing, 100730, China.
- National Clinical Research Center for Dermatologic and Immunologic Diseases, Beijing, China.
| |
Collapse
|
10
|
Hu M, Alkhairy S, Lee I, Pillich RT, Fong D, Smith K, Bachelder R, Ideker T, Pratt D. Evaluation of large language models for discovery of gene set function. Nat Methods 2025; 22:82-91. [PMID: 39609565 PMCID: PMC11725441 DOI: 10.1038/s41592-024-02525-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2023] [Accepted: 10/21/2024] [Indexed: 11/30/2024]
Abstract
Gene set enrichment is a mainstay of functional genomics, but it relies on gene function databases that are incomplete. Here we evaluate five large language models (LLMs) for their ability to discover the common functions represented by a gene set, supported by molecular rationale and a self-confidence assessment. For curated gene sets from Gene Ontology, GPT-4 suggests functions similar to the curated name in 73% of cases, with higher self-confidence predicting higher similarity. Conversely, random gene sets correctly yield zero confidence in 87% of cases. Other LLMs (GPT-3.5, Gemini Pro, Mixtral Instruct and Llama2 70b) vary in function recovery but are falsely confident for random sets. In gene clusters from omics data, GPT-4 identifies common functions for 45% of cases, fewer than functional enrichment but with higher specificity and gene coverage. Manual review of supporting rationale and citations finds these functions are largely verifiable. These results position LLMs as valuable omics assistants.
Collapse
Affiliation(s)
- Mengzhou Hu
- Department of Medicine, University of California San Diego, La Jolla, CA, USA
| | - Sahar Alkhairy
- Department of Computer Science and Engineering, University of California San Diego, La Jolla, CA, USA
| | - Ingoo Lee
- Department of Medicine, University of California San Diego, La Jolla, CA, USA
| | - Rudolf T Pillich
- Department of Medicine, University of California San Diego, La Jolla, CA, USA
| | - Dylan Fong
- Department of Medicine, University of California San Diego, La Jolla, CA, USA
| | - Kevin Smith
- Department of Physics, University of California San Diego, La Jolla, CA, USA
| | - Robin Bachelder
- Department of Medicine, University of California San Diego, La Jolla, CA, USA
| | - Trey Ideker
- Department of Medicine, University of California San Diego, La Jolla, CA, USA.
- Department of Computer Science and Engineering, University of California San Diego, La Jolla, CA, USA.
| | - Dexter Pratt
- Department of Medicine, University of California San Diego, La Jolla, CA, USA.
| |
Collapse
|
11
|
Alakhdar AA, Sivakumar S, Kopchak RM, Hunter AN, Ambrosio F, Washburn NR. Age-Related ECM Stiffness Mediates TRAIL Activation in Muscle Stem Cell Differentiation. Adv Biol (Weinh) 2024; 8:e2400334. [PMID: 39601528 PMCID: PMC11889993 DOI: 10.1002/adbi.202400334] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2024] [Revised: 10/01/2024] [Indexed: 11/29/2024]
Abstract
The stiffening of the extracellular matrix (ECM) with age hinders muscle regeneration by causing intrinsic muscle stem cell (MuSC) dysfunction through a poorly understood mechanism. Here, the study aims to study those age-related molecular changes in the differentiation of MuSCs due to age and/or stiffness. Hence, young and aged MuSCs are seeded onto substrates engineered to mimic a soft and stiff ECM microenvironment to study those molecular changes using single-cell RNA sequencing (scRNA). The trajectory of scRNA data of the MuSCs under four different conditions undergoing differentiation is analyzed as well as the active molecular pathways and transcription factors driving those differentiation fates. Data revealed the presence of a branching point within the trajectory leading to the emergence of an age-related fibroblastic population characterized by activation of the TNF-related apoptosis-inducing ligand (TRAIL) pathway, which is significantly activated in aged cells cultured on stiff substrates. Next, using the collagen cross-linking inhibitor β-aminopropionitrile (BAPN) in vivo, the study elucidates stiffness changes on TRAIL downstream apoptotic targets (caspase 8 and caspase 3) using immunostaining. TRAIL activity is significantly inhibited by BAPN in aged animals, indicating a complex mechanism of age-related declines in muscle function through inflammatory and apoptotic mediators.
Collapse
Affiliation(s)
- Amira A. Alakhdar
- Department of Chemistry, Carnegie Mellon University, Pittsburgh, PA, 15213, USA
| | | | - Rylee M. Kopchak
- Discovery Center for Musculoskeletal Recovery, Schoen Adams Research Institute at Spaulding, Boston, MA, USA
| | - Allison N. Hunter
- Department of Biomedical Engineering, Carnegie Mellon University, Pittsburgh, PA, 15213, USA
| | - Fabrisia Ambrosio
- Discovery Center for Musculoskeletal Recovery, Schoen Adams Research Institute at Spaulding, Boston, MA, USA
- Department of Physical Medicine & Rehabilitation, Spaulding Rehabilitation Hospital, Harvard Medical School, Boston, MA, USA
| | - Newell R. Washburn
- Department of Chemistry, Carnegie Mellon University, Pittsburgh, PA, 15213, USA
- Department of Biomedical Engineering, Carnegie Mellon University, Pittsburgh, PA, 15213, USA
| |
Collapse
|
12
|
Rediti M, Venet D, Joaquin Garcia A, Maetens M, Vincent D, Majjaj S, El-Abed S, Di Cosimo S, Ueno T, Izquierdo M, Piccart M, Pusztai L, Loi S, Salgado R, Viale G, Rothé F, Sotiriou C. Identification of HER2-positive breast cancer molecular subtypes with potential clinical implications in the ALTTO clinical trial. Nat Commun 2024; 15:10402. [PMID: 39613746 PMCID: PMC11607438 DOI: 10.1038/s41467-024-54621-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2024] [Accepted: 11/13/2024] [Indexed: 12/01/2024] Open
Abstract
In HER2-positive breast cancer, clinical outcome and sensitivity to HER2-targeted therapies are influenced by both tumor and microenvironment features. However, we are currently unable to depict the molecular heterogeneity of this disease with sufficient granularity. Here, by performing gene expression profiling in HER2-positive breast cancers from patients receiving adjuvant trastuzumab in the ALTTO clinical trial (NCT00490139), we identify and characterize five molecular subtypes associated with the risk of distant recurrence: immune-enriched, proliferative/metabolic-enriched, mesenchymal/stroma-enriched, luminal, and ERBB2-dependent. Additionally, we validate the biological profiles of the subtypes and explore their prognostic/predictive value in external cohorts, namely the NeoALTTO trial (NCT00553358), SCAN-B (NCT02306096), I-SPY2 (NCT01042379), METABRIC and TCGA. Immune-enriched tumors present better survival outcomes, in contrast to mesenchymal/stroma-enriched and proliferative/metabolic-enriched tumors, while luminal and ERBB2-dependent tumors are characterized by low and high rates of pathological complete response, respectively. Of note, these molecular subtypes provide the rationale for treatment approaches leveraging the heterogeneous biology of HER2-positive breast cancer.
Collapse
Affiliation(s)
- Mattia Rediti
- Breast Cancer Translational Research Laboratory, Institut Jules Bordet, Hôpital Universitaire de Bruxelles (H.U.B), Université Libre de Bruxelles (ULB), Brussels, Belgium
- IFOM ETS, the AIRC Institute of Molecular Oncology, Milan, Italy
| | - David Venet
- Breast Cancer Translational Research Laboratory, Institut Jules Bordet, Hôpital Universitaire de Bruxelles (H.U.B), Université Libre de Bruxelles (ULB), Brussels, Belgium
| | - Andrea Joaquin Garcia
- Breast Cancer Translational Research Laboratory, Institut Jules Bordet, Hôpital Universitaire de Bruxelles (H.U.B), Université Libre de Bruxelles (ULB), Brussels, Belgium
| | - Marion Maetens
- Laboratory for Translational Breast Cancer Research, KU Leuven, Leuven, Belgium
| | - Delphine Vincent
- Breast Cancer Translational Research Laboratory, Institut Jules Bordet, Hôpital Universitaire de Bruxelles (H.U.B), Université Libre de Bruxelles (ULB), Brussels, Belgium
| | - Samira Majjaj
- Breast Cancer Translational Research Laboratory, Institut Jules Bordet, Hôpital Universitaire de Bruxelles (H.U.B), Université Libre de Bruxelles (ULB), Brussels, Belgium
| | | | - Serena Di Cosimo
- Department of Advanced Diagnostics, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Takayuki Ueno
- Breast Surgical Oncology, Breast Oncology Center, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan
| | | | - Martine Piccart
- Institut Jules Bordet, Hôpital Universitaire de Bruxelles (H.U.B), Université Libre de Bruxelles (ULB), Brussels, Belgium
| | - Lajos Pusztai
- Yale School of Medicine, Yale Cancer Center, New Haven, CT, USA
| | - Sherene Loi
- Division of Cancer Research, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia
- The Sir Peter MacCallum Department of Medical Oncology, The University of Melbourne, Parkville, VIC, Australia
| | - Roberto Salgado
- Division of Cancer Research, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia
- Department of Pathology, ZAS Hospitals, Antwerp, Belgium
| | - Giuseppe Viale
- Division of Pathology, IEO, European Institute of Oncology IRCCS, Milan, Italy
| | - Françoise Rothé
- Breast Cancer Translational Research Laboratory, Institut Jules Bordet, Hôpital Universitaire de Bruxelles (H.U.B), Université Libre de Bruxelles (ULB), Brussels, Belgium
| | - Christos Sotiriou
- Breast Cancer Translational Research Laboratory, Institut Jules Bordet, Hôpital Universitaire de Bruxelles (H.U.B), Université Libre de Bruxelles (ULB), Brussels, Belgium.
| |
Collapse
|
13
|
Cohen CA, Zumbrun EE, Writer JV, Bonagofski LG, Shoemaker CJ, Zeng X, Blancett CD, Douglas CE, Delp KL, Taylor-Howell CL, Carey BD, Ravulapalli S, Raymond JL, Dye JM, Herbert AS. A Small-Particle Aerosol Model of Ebolavirus Zaire Infection in Ferrets. Viruses 2024; 16:1806. [PMID: 39772117 PMCID: PMC11680438 DOI: 10.3390/v16121806] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2024] [Revised: 11/12/2024] [Accepted: 11/15/2024] [Indexed: 01/11/2025] Open
Abstract
The Ebola virus (EBOV) causes severe disease in humans, and animal models are needed to evaluate the efficacy of vaccines and therapeutics. While non-human primate (NHP) and rodent EBOV infection models have been well characterized, there is a growing need for an intermediate model. Here, we provide the first report of a small-particle aerosol (AE) EBOV ferret model and disease progression compared with the intramuscular (IM) EBOV ferret model. EBOV infection of ferrets by either route resulted in uniform lethality in 5-6.5 days post infection (dpi) in a dose-dependent manner, with IM-infected ferrets succumbing significantly earlier than AE-infected ferrets. EBOV disease progression differed between AE and IM routes, with significant viremia and presence of virus in target organs occurring earlier in the AE model. In contrast, significant fever, clinical signs of disease, liver pathology, and systemic inflammation occurred earlier in the IM EBOV model. Hepatocellular damage and splenic pathology were noted in both models, while pronounced lung pathology and renal impairment were exclusive to the AE and IM models, respectively. These results demonstrate that small-particle AE and IM ferret EBOV models share numerous common features with NHP and human EBOV infection by these routes and will therefore be useful for the development of vaccine and therapeutic countermeasures.
Collapse
Affiliation(s)
- Courtney A. Cohen
- Viral Immunology Branch, Virology Division, U.S. Army Medical Research Institute of Infectious Diseases, Frederick, MD 21702, USA; (C.A.C.); (E.E.Z.); (J.M.D.)
| | - Elizabeth E. Zumbrun
- Viral Immunology Branch, Virology Division, U.S. Army Medical Research Institute of Infectious Diseases, Frederick, MD 21702, USA; (C.A.C.); (E.E.Z.); (J.M.D.)
| | - James V. Writer
- Regulated Research Administration Division, U.S. Army Medical Research Institute of Infectious Diseases, Frederick, MD 21702, USA;
| | - Luke G. Bonagofski
- Viral Immunology Branch, Virology Division, U.S. Army Medical Research Institute of Infectious Diseases, Frederick, MD 21702, USA; (C.A.C.); (E.E.Z.); (J.M.D.)
| | - Charles J. Shoemaker
- Diagnostics System Division, U.S. Army Medical Research Institute of Infectious Diseases, Frederick, MD 21702, USA; (C.J.S.); (C.D.B.); (K.L.D.); (C.L.T.-H.); (B.D.C.); (S.R.)
| | - Xiankun Zeng
- Pathology Division, U.S. Army Medical Research Institute of Infectious Diseases, Frederick, MD 21702, USA; (X.Z.); (J.L.R.)
| | - Candace D. Blancett
- Diagnostics System Division, U.S. Army Medical Research Institute of Infectious Diseases, Frederick, MD 21702, USA; (C.J.S.); (C.D.B.); (K.L.D.); (C.L.T.-H.); (B.D.C.); (S.R.)
| | - Christina E. Douglas
- Diagnostics System Division, U.S. Army Medical Research Institute of Infectious Diseases, Frederick, MD 21702, USA; (C.J.S.); (C.D.B.); (K.L.D.); (C.L.T.-H.); (B.D.C.); (S.R.)
| | - Korey L. Delp
- Diagnostics System Division, U.S. Army Medical Research Institute of Infectious Diseases, Frederick, MD 21702, USA; (C.J.S.); (C.D.B.); (K.L.D.); (C.L.T.-H.); (B.D.C.); (S.R.)
| | - Cheryl L. Taylor-Howell
- Diagnostics System Division, U.S. Army Medical Research Institute of Infectious Diseases, Frederick, MD 21702, USA; (C.J.S.); (C.D.B.); (K.L.D.); (C.L.T.-H.); (B.D.C.); (S.R.)
| | - Brian D. Carey
- Diagnostics System Division, U.S. Army Medical Research Institute of Infectious Diseases, Frederick, MD 21702, USA; (C.J.S.); (C.D.B.); (K.L.D.); (C.L.T.-H.); (B.D.C.); (S.R.)
| | - Suma Ravulapalli
- Diagnostics System Division, U.S. Army Medical Research Institute of Infectious Diseases, Frederick, MD 21702, USA; (C.J.S.); (C.D.B.); (K.L.D.); (C.L.T.-H.); (B.D.C.); (S.R.)
| | - Jo Lynne Raymond
- Pathology Division, U.S. Army Medical Research Institute of Infectious Diseases, Frederick, MD 21702, USA; (X.Z.); (J.L.R.)
| | - John M. Dye
- Viral Immunology Branch, Virology Division, U.S. Army Medical Research Institute of Infectious Diseases, Frederick, MD 21702, USA; (C.A.C.); (E.E.Z.); (J.M.D.)
| | - Andrew S. Herbert
- Viral Immunology Branch, Virology Division, U.S. Army Medical Research Institute of Infectious Diseases, Frederick, MD 21702, USA; (C.A.C.); (E.E.Z.); (J.M.D.)
| |
Collapse
|
14
|
Ankill J, Zhao Z, Tekpli X, Kure EH, Kristensen VN, Mathelier A, Fleischer T. Integrative pan-cancer analysis reveals a common architecture of dysregulated transcriptional networks characterized by loss of enhancer methylation. PLoS Comput Biol 2024; 20:e1012565. [PMID: 39556603 DOI: 10.1371/journal.pcbi.1012565] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2024] [Accepted: 10/16/2024] [Indexed: 11/20/2024] Open
Abstract
Aberrant DNA methylation contributes to gene expression deregulation in cancer. However, these alterations' precise regulatory role and clinical implications are still not fully understood. In this study, we performed expression-methylation Quantitative Trait Loci (emQTL) analysis to identify deregulated cancer-driving transcriptional networks linked to CpG demethylation pan-cancer. By analyzing 33 cancer types from The Cancer Genome Atlas, we identified and confirmed significant correlations between CpG methylation and gene expression (emQTL) in cis and trans, both across and within cancer types. Bipartite network analysis of the emQTL revealed groups of CpGs and genes related to important biological processes involved in carcinogenesis including proliferation, metabolism and hormone-signaling. These bipartite communities were characterized by loss of enhancer methylation in specific transcription factor binding regions (TFBRs) and the CpGs were topologically linked to upregulated genes through chromatin loops. Penalized Cox regression analysis showed a significant prognostic impact of the pan-cancer emQTL in many cancer types. Taken together, our integrative pan-cancer analysis reveals a common architecture where hallmark cancer-driving functions are affected by the loss of enhancer methylation and may be epigenetically regulated.
Collapse
Affiliation(s)
- Jørgen Ankill
- Department of Cancer Genetics, Institute of Cancer Research, Oslo University Hospital, Oslo, Norway
- Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway
| | - Zhi Zhao
- Department of Cancer Genetics, Institute of Cancer Research, Oslo University Hospital, Oslo, Norway
- Oslo Centre for Biostatistics and Epidemiology (OCBE), Faculty of Medicine, University of Oslo, Oslo, Norway
| | - Xavier Tekpli
- Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway
| | - Elin H Kure
- Department of Cancer Genetics, Institute of Cancer Research, Oslo University Hospital, Oslo, Norway
| | - Vessela N Kristensen
- Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway
- Department of Medical Genetics, Institute of Clinical Medicine, University of Oslo and Oslo University Hospital, Oslo, Norway
| | - Anthony Mathelier
- Department of Medical Genetics, Institute of Clinical Medicine, University of Oslo and Oslo University Hospital, Oslo, Norway
- Centre for Molecular Medicine Norway (NCMM), Nordic EMBL Partnership, University of Norway, Oslo, Norway
| | - Thomas Fleischer
- Department of Cancer Genetics, Institute of Cancer Research, Oslo University Hospital, Oslo, Norway
| |
Collapse
|
15
|
Singh H, Nair A, Mahajan SD. Impact of genetic variations of gene involved in regulation of metabolism, inflammation and coagulation on pathogenesis of cardiac injuries associated with COVID-19. Pathol Res Pract 2024; 263:155608. [PMID: 39447244 DOI: 10.1016/j.prp.2024.155608] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/08/2024] [Revised: 08/29/2024] [Accepted: 09/24/2024] [Indexed: 10/26/2024]
Abstract
BACKGROUND SARS-CoV-2 infection can result in long-term chronic cardiovascular (CV) damage after the acute phase of the illness. COVID-19 frequently causes active myocarditis, SARS-CoV-2 can directly infect and kill cardiac cells, causing severe pathology and dysfunction across the organs and cells. Till now, the pathogenesis of COVID-19-associated cardiac injuries has not been understood, but there are several factors that contribute to the progression of cardiac injuries, such as genetic, dietary, and environmental. Among them ranges of host genetic factor including metabolizing, inflammation, and coagulation related genes have a role to contribute the cardiac injuries induced by COVID-19. Hereditary DNA sequence variations contribute to the risk of illness in almost all of these diseases. Hence, we comprehended the occurrence of genetic variations of metabolizing, inflammation and coagulation-related genes in the general population, their expression in various diseases, and their impact on cardiac injuries induced by COVID-19. METHOD We utilized multiple databases, including PubMed (Medline), EMBASE, and Google Scholar, for literature searches. DESCRIPTION The genes involved in metabolism (APOE, MTHFR), coagulation (PAI-1, ACE2), and immune factors (CRP, ESR, and troponin I) may have a role in the progression of COVID-19-associated cardiac injuries. The risk factors for CVD are significantly varied between and within different regions. In healthy individuals, the ACE I allele is responsible for the predisposition to CAD, but the ACE D haplotype is responsible for susceptibility and severity, which ultimately leads to heart failure. Patients who carry the T allele of rs12329760 in the TMPRSS2 gene are at risk for developing the severe form of COVID-19. IL-6 (rs1800796/rs1800795) polymorphism is associated with an increased mortality rate and susceptibility to severe COVID-19 disease. While the putative role of IL-6 associated with chronic, inflammatory diseases like cardiac and cerebrovascular disease is well known. CONCLUSION The occurrence of genetic variations in the ACE-2, AGT, DPP-IV, TMPRSS2, FUIRN, IL-4, IL-6, IFN-γ, and CYP2D6 genes is varied among different populations. Examining the correlation between these variations and their protein levels and cardiac injuries induced by COVID-19 may provide valuable insights into the pathogenesis of cardiac injuries induced by COVID-19.
Collapse
Affiliation(s)
- HariOm Singh
- Department of Molecular Biology, National AIDS Research Institute, Pune 411026, India.
| | - Aishwarya Nair
- Department of Molecular Biology, National AIDS Research Institute, Pune 411026, India
| | - Supriya D Mahajan
- Department of Medicine, Jacobs School of Medicine & Biomedical Sciences, University at Buffalo's Clinical Translational Research Center, 875 Ellicott Street, Buffalo, NY 14203, USA
| |
Collapse
|
16
|
Lacinski RA, Dziadowicz SA, Roth CA, Ma L, Melemai VK, Fitzpatrick B, Chaharbakhshi E, Heim T, Lohse I, Schoedel KE, Hu G, Llosa NJ, Weiss KR, Lindsey BA. Proteomic and transcriptomic analyses identify apo-transcobalamin-II as a biomarker of overall survival in osteosarcoma. Front Oncol 2024; 14:1417459. [PMID: 39493449 PMCID: PMC11527601 DOI: 10.3389/fonc.2024.1417459] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2024] [Accepted: 09/17/2024] [Indexed: 11/05/2024] Open
Abstract
Background The large-scale proteomic platform known as the SomaScan® assay is capable of simultaneously measuring thousands of proteins in patient specimens through next-generation aptamer-based multiplexed technology. While previous studies have utilized patient peripheral blood to suggest serum biomarkers of prognostic or diagnostic value in osteosarcoma (OSA), the most common primary pediatric bone cancer, they have ultimately been limited in the robustness of their analyses. We propose utilizing this aptamer-based technology to describe the systemic proteomic milieu in patients diagnosed with this disease. Methods To determine novel biomarkers associated with overall survival in OSA, we deployed the SomaLogic SomaScan® 7k assay to investigate the plasma proteomic profile of naive primary, recurrent, and metastatic OSA patients. Following identification of differentially expressed proteins (DEPs) between 2-year deceased and survivor cohorts, publicly available databases including Survival Genie, TIGER, and KM Plotter Immunotherapy, among others, were utilized to investigate the significance of our proteomic findings. Results Apo-transcobalamin-II (APO-TCN2) was identified as the most DEP between 2-year deceased and survivor cohorts (Log2 fold change = 6.8, P-value = 0.0017). Survival analysis using the Survival Genie web-based platform indicated that increased intratumoral TCN2 expression was associated with better overall survival in both OSA (TARGET-OS) and sarcoma (TCGA-SARC) datasets. Cell-cell communication analysis using the TIGER database suggested that TCN2+ Myeloid cells likely interact with marginal zone and immunoglobin-producing B lymphocytes expressing the TCN2 receptor (CD320) to promote their proliferation and survival in both non-small cell lung cancer and melanoma tumors. Analysis of publicly available OSA scRNA-sequencing datasets identified similar populations in naive primary tumors. Furthermore, circulating APO-TCN2 levels in OSA were then associated with a plasma proteomic profile likely necessary for robust B lymphocyte proliferation, infiltration, and formation of intratumoral tertiary lymphoid structures for improved anti-tumor immunity. Conclusions Overall, APO-TCN2, a circulatory protein previously described in various lymphoproliferative disorders, was associated with 2-year survival status in patients diagnosed with OSA. The relevance of this protein and apparent immunological function (anti-tumor B lymphocyte responses) was suggested using publicly available solid tumor RNA-sequencing datasets. Further studies characterizing the biological function of APO-TCN2 and its relevance in these diseases is warranted.
Collapse
Affiliation(s)
- Ryan A. Lacinski
- Department of Orthopaedics, West Virginia University School of Medicine, Morgantown, WV, United States
- West Virginia University Cancer Institute, West Virginia University School of Medicine, Morgantown, WV, United States
| | - Sebastian A. Dziadowicz
- Department of Microbiology, Immunology, and Cell Biology, West Virginia University School of Medicine, Morgantown, WV, United States
- Bioinformatics Core, West Virginia University School of Medicine, Morgantown, WV, United States
| | - Clark A. Roth
- Department of Orthopaedic Surgery, University of Pittsburgh, Pittsburgh, PA, United States
| | - Li Ma
- Department of Microbiology, Immunology, and Cell Biology, West Virginia University School of Medicine, Morgantown, WV, United States
- Bioinformatics Core, West Virginia University School of Medicine, Morgantown, WV, United States
| | - Vincent K. Melemai
- Department of Orthopaedics, West Virginia University School of Medicine, Morgantown, WV, United States
| | - Brody Fitzpatrick
- Department of Orthopaedics, West Virginia University School of Medicine, Morgantown, WV, United States
| | - Edwin Chaharbakhshi
- Department of Orthopaedics, West Virginia University School of Medicine, Morgantown, WV, United States
| | - Tanya Heim
- Department of Orthopaedic Surgery, University of Pittsburgh, Pittsburgh, PA, United States
| | - Ines Lohse
- Department of Orthopaedic Surgery, University of Pittsburgh, Pittsburgh, PA, United States
| | - Karen E. Schoedel
- Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, PA, United States
| | - Gangqing Hu
- Department of Microbiology, Immunology, and Cell Biology, West Virginia University School of Medicine, Morgantown, WV, United States
- Bioinformatics Core, West Virginia University School of Medicine, Morgantown, WV, United States
| | - Nicolas J. Llosa
- Department of Orthopaedic Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, United States
| | - Kurt R. Weiss
- Department of Orthopaedic Surgery, University of Pittsburgh, Pittsburgh, PA, United States
| | - Brock A. Lindsey
- Department of Orthopaedic Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, United States
| |
Collapse
|
17
|
Fischer SN, Claussen ER, Kourtis S, Sdelci S, Orchard S, Hermjakob H, Kustatscher G, Drew K. hu.MAP3.0: Atlas of human protein complexes by integration of > 25,000 proteomic experiments. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.10.11.617930. [PMID: 39464102 PMCID: PMC11507723 DOI: 10.1101/2024.10.11.617930] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Indexed: 10/29/2024]
Abstract
Macromolecular protein complexes carry out most functions in the cell including essential functions required for cell survival. Unfortunately, we lack the subunit composition for all human protein complexes. To address this gap we integrated >25,000 mass spectrometry experiments using a machine learning approach to identify > 15,000 human protein complexes. We show our map of protein complexes is highly accurate and more comprehensive than previous maps, placing ~75% of human proteins into their physical contexts. We globally characterize our complexes using protein co-variation data (ProteomeHD.2) and identify co-varying complexes suggesting common functional associations. Our map also generates testable functional hypotheses for 472 uncharacterized proteins which we support using AlphaFold modeling. Additionally, we use AlphaFold modeling to identify 511 mutually exclusive protein pairs in hu.MAP3.0 complexes suggesting complexes serve different functional roles depending on their subunit composition. We identify expression as the primary way cells and organisms relieve the conflict of mutually exclusive subunits. Finally, we import our complexes to EMBL-EBI's Complex Portal (https://www.ebi.ac.uk/complexportal/home) as well as provide complexes through our hu.MAP3.0 web interface (https://humap3.proteincomplexes.org/). We expect our resource to be highly impactful to the broader research community.
Collapse
Affiliation(s)
- Samantha N. Fischer
- Department of Biological Sciences, University of Illinois at Chicago, Chicago, IL 60607
| | - Erin R. Claussen
- Department of Biological Sciences, University of Illinois at Chicago, Chicago, IL 60607
| | - Savvas Kourtis
- Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Barcelona, Spain
| | - Sara Sdelci
- Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Barcelona, Spain
| | - Sandra Orchard
- European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI), Wellcome Genome Campus, Hinxton, Cambridge CB10 1SD, UK
| | - Henning Hermjakob
- European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI), Wellcome Genome Campus, Hinxton, Cambridge CB10 1SD, UK
| | - Georg Kustatscher
- Wellcome Centre for Cell Biology, University of Edinburgh, Edinburgh EH9 3BF, UK
| | - Kevin Drew
- Department of Biological Sciences, University of Illinois at Chicago, Chicago, IL 60607
| |
Collapse
|
18
|
Mori LP, Corley MJ, McAuley AT, Pang A, Venables T, Ndhlovu LC, Pipkin ME, Valente ST. Transcriptional and methylation outcomes of didehydro-cortistatin A use in HIV-1-infected CD4 + T cells. Life Sci Alliance 2024; 7:e202402653. [PMID: 39089880 PMCID: PMC11294679 DOI: 10.26508/lsa.202402653] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2024] [Revised: 07/20/2024] [Accepted: 07/22/2024] [Indexed: 08/04/2024] Open
Abstract
Ongoing viral transcription from the reservoir of HIV-1 infected long-lived memory CD4+ T cells presents a barrier to cure and associates with poorer health outcomes for people living with HIV, including chronic immune activation and inflammation. We previously reported that didehydro-cortistatin A (dCA), an HIV-1 Tat inhibitor, blocks HIV-1 transcription. Here, we examine the impact of dCA on host immune CD4+ T-cell transcriptional and epigenetic states. We performed a comprehensive analysis of genome-wide transcriptomic and DNA methylation profiles upon long-term dCA treatment of primary human memory CD4+ T cells. dCA prompted specific transcriptional and DNA methylation changes in cell cycle, histone, interferon-response, and T-cell lineage transcription factor genes, through inhibition of both HIV-1 and Mediator kinases. These alterations establish a tolerogenic Treg/Th2 phenotype, reducing viral gene expression and mitigating inflammation in primary CD4+ T cells during HIV-1 infection. In addition, dCA suppresses the expression of lineage-defining transcription factors for Th17 and Th1 cells, critical HIV-1 targets, and reservoirs. dCA's benefits thus extend beyond viral transcription inhibition, modulating the immune cell landscape to limit HIV-1 acquisition and inflammatory environment linked to HIV infection.
Collapse
Affiliation(s)
- Luisa P Mori
- The Skaggs Graduate School of Chemical and Biological Sciences, The Scripps Research Institute, Jupiter, FL, USA
- Department of Immunology and Microbiology, The Herbert Wertheim UF Scripps Institute for Biomedical Innovation & Technology, Jupiter, FL, USA
| | - Michael J Corley
- Department of Medicine, Division of Infectious Diseases, Weill Cornell Medicine, New York, NY, USA
| | - Andrew T McAuley
- Department of Immunology and Microbiology, The Herbert Wertheim UF Scripps Institute for Biomedical Innovation & Technology, Jupiter, FL, USA
| | - Alina Pang
- Department of Medicine, Division of Infectious Diseases, Weill Cornell Medicine, New York, NY, USA
| | - Thomas Venables
- Department of Immunology and Microbiology, The Herbert Wertheim UF Scripps Institute for Biomedical Innovation & Technology, Jupiter, FL, USA
| | - Lishomwa C Ndhlovu
- Department of Medicine, Division of Infectious Diseases, Weill Cornell Medicine, New York, NY, USA
| | - Matthew E Pipkin
- The Skaggs Graduate School of Chemical and Biological Sciences, The Scripps Research Institute, Jupiter, FL, USA
- Department of Immunology and Microbiology, The Herbert Wertheim UF Scripps Institute for Biomedical Innovation & Technology, Jupiter, FL, USA
| | - Susana T Valente
- The Skaggs Graduate School of Chemical and Biological Sciences, The Scripps Research Institute, Jupiter, FL, USA
- Department of Immunology and Microbiology, The Herbert Wertheim UF Scripps Institute for Biomedical Innovation & Technology, Jupiter, FL, USA
| |
Collapse
|
19
|
Grunwell JR, Huang M, Stephenson ST, Tidwell M, Ripple MJ, Fitzpatrick AM, Kamaleswaran R. RNA Sequencing Analysis of Monocytes Exposed to Airway Fluid From Children With Pediatric Acute Respiratory Distress Syndrome. Crit Care Explor 2024; 6:e1125. [PMID: 39365167 PMCID: PMC11458172 DOI: 10.1097/cce.0000000000001125] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/05/2024] Open
Abstract
OBJECTIVES Monocytes are plastic cells that assume different polarization states that can either promote inflammation or tissue repair and inflammation resolution. Polarized monocytes are partially defined by their transcriptional profiles that are influenced by environmental stimuli. The airway monocyte response in pediatric acute respiratory distress syndrome (PARDS) is undefined. To identify differentially expressed genes and networks using a novel transcriptomic reporter assay with donor monocytes exposed to the airway fluid of intubated children with and at-risk for PARDS. To determine differences in gene expression at two time points using the donor monocyte assay exposed to airway fluid from intubated children with PARDS obtained 48-96 hours following initial tracheal aspirate sampling. DESIGN In vitro pilot study carried out using airway fluid supernatant. SETTING Academic 40-bed PICU. PARTICIPANTS Fifty-seven children: 44 children with PARDS and 13 children at-risk for PARDS. INTERVENTIONS None. MEASUREMENTS AND MAIN RESULTS We performed bulk RNA sequencing using a transcriptomic reporter assay of monocytes exposed to airway fluid from intubated children to discover gene networks differentiating PARDS from at-risk for PARDS and those differentiating mild/moderate from severe PARDS. We also report differences in gene expression in children with PARDS 48-96 hours following initial tracheal aspirate sampling. We found that interleukin (IL)-10, IL-4, and IL-13, cytokine/chemokine signaling, and the senescence-associated secretory phenotype are upregulated in monocytes exposed to airway fluid from intubated children with PARDS compared with those at-risk for PARDS. Signaling by NOTCH, histone deacetylation/acetylation, DNA methylation, chromatin modifications (B-WICH complex), and RNA polymerase I transcription and its associated regulatory apparatus were upregulated in children with PARDS 48-96 hours following initial tracheal aspirate sampling. CONCLUSIONS We identified gene networks important to the PARDS airway immune response using bulk RNA sequencing from a monocyte reporter assay that exposed monocytes to airway fluid from intubated children with and at-risk for PARDS. Mechanistic investigations are needed to validate our findings.
Collapse
Affiliation(s)
- Jocelyn R. Grunwell
- Department of Pediatrics/Division of Critical Care Medicine, Egleston Hospital, Children’s Healthcare of Atlanta, Atlanta, GA
- Department of Pediatrics, Emory University School of Medicine, Atlanta, GA
| | - Min Huang
- Department of Biomedical Informatics, Emory University School of Medicine, Atlanta, GA
| | | | - Mallory Tidwell
- Department of Pediatrics/Division of Critical Care Medicine, Egleston Hospital, Children’s Healthcare of Atlanta, Atlanta, GA
| | - Michael J. Ripple
- Department of Pediatrics/Division of Critical Care Medicine, Egleston Hospital, Children’s Healthcare of Atlanta, Atlanta, GA
- Department of Pediatrics, Emory University School of Medicine, Atlanta, GA
| | - Anne M. Fitzpatrick
- Department of Pediatrics/Division of Critical Care Medicine, Egleston Hospital, Children’s Healthcare of Atlanta, Atlanta, GA
- Department of Pediatrics, Emory University School of Medicine, Atlanta, GA
| | - Rishikesan Kamaleswaran
- Department of Pediatrics, Emory University School of Medicine, Atlanta, GA
- Department of Biomedical Informatics, Emory University School of Medicine, Atlanta, GA
- Department of Biomedical Engineering, Georgia Institute of Technology, Atlanta, GA
| |
Collapse
|
20
|
Luo H, Petrera A, Hauck SM, Rathmann W, Herder C, Gieger C, Hoyer A, Peters A, Thorand B. Association of plasma proteomics with mortality in individuals with and without type 2 diabetes: Results from two population-based KORA cohort studies. BMC Med 2024; 22:420. [PMID: 39334377 PMCID: PMC11438072 DOI: 10.1186/s12916-024-03636-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/03/2024] [Accepted: 09/13/2024] [Indexed: 09/30/2024] Open
Abstract
BACKGROUND Protein biomarkers may contribute to the identification of vulnerable subgroups for premature mortality. This study aimed to investigate the association of plasma proteins with all-cause and cause-specific mortality among individuals with and without baseline type 2 diabetes (T2D) and evaluate their impact on the prediction of all-cause mortality in two prospective Cooperative Health Research in the Region of Augsburg (KORA) studies. METHODS The discovery cohort comprised 1545 participants (median follow-up 15.6 years; 244 with T2D: 116 total, 62 cardiovascular, 31 cancer-related and 23 other-cause deaths; 1301 without T2D: 321 total, 114 cardiovascular, 120 cancer-related and 87 other-cause deaths). The validation cohort comprised 1031 participants (median follow-up 6.9 years; 203 with T2D: 76 total, 45 cardiovascular, 19 cancer-related and 12 other-cause deaths; 828 without T2D: 169 total, 74 cardiovascular, 39 cancer-related and 56 other-cause deaths). We used Cox regression to examine associations of 233 plasma proteins with all-cause and cause-specific mortality and Lasso regression to construct prediction models for all-cause mortality stratifying by baseline T2D. C-index, category-free net reclassification index (cfNRI), and integrated discrimination improvement (IDI) were conducted to evaluate the predictive performance of built prediction models. RESULTS Thirty-five and 62 proteins, with 29 overlapping, were positively associated with all-cause mortality in the group with and without T2D, respectively. Out of these, in the group with T2D, 35, eight, and 26 were positively associated with cardiovascular, cancer-related, and other-cause mortality, while in the group without T2D, 55, 41, and 47 were positively associated with respective cause-specific outcomes in the pooled analysis of both cohorts. Regulation of insulin-like growth factor (IGF) transport and uptake by IGF-binding proteins emerged as a unique pathway enriched for all-cause and cardiovascular mortality in individuals with T2D. The combined model containing the selected proteins (five and 12 proteins, with four overlapping, in the group with and without T2D, respectively) and clinical risk factors improved the prediction of all-cause mortality by C-index, cfNRI, and IDI. CONCLUSIONS This study uncovered shared and unique mortality-related proteins in persons with and without T2D and emphasized the role of proteins in improving the prediction of mortality in different T2D subgroups.
Collapse
Affiliation(s)
- Hong Luo
- Institute of Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), Neuherberg, Germany
- Institute for Medical Information Processing, Biometry and Epidemiology (IBE), Faculty of Medicine, Pettenkofer School of Public Health, LMU Munich, Munich, Germany
| | - Agnese Petrera
- Metabolomics and Proteomics Core, Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), Neuherberg, Germany
| | - Stefanie M Hauck
- Metabolomics and Proteomics Core, Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), Neuherberg, Germany
- German Center for Diabetes Research (DZD), Partner München-Neuherberg, Neuherberg, Germany
| | - Wolfgang Rathmann
- Institute for Biometrics and Epidemiology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University, Düsseldorf, Germany
- German Center for Diabetes Research (DZD), Partner Düsseldorf, Neuherberg, Germany
| | - Christian Herder
- German Center for Diabetes Research (DZD), Partner Düsseldorf, Neuherberg, Germany
- Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University, Düsseldorf, Germany
- Department of Endocrinology and Diabetology, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University, Düsseldorf, Germany
| | - Christian Gieger
- Institute of Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), Neuherberg, Germany
- German Center for Diabetes Research (DZD), Partner München-Neuherberg, Neuherberg, Germany
- Research Unit of Molecular Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), Neuherberg, Germany
| | - Annika Hoyer
- Biostatistics and Medical Biometry, Medical School OWL, Bielefeld University, Bielefeld, Germany
| | - Annette Peters
- Institute of Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), Neuherberg, Germany
- Institute for Medical Information Processing, Biometry and Epidemiology (IBE), Faculty of Medicine, Pettenkofer School of Public Health, LMU Munich, Munich, Germany
- German Center for Diabetes Research (DZD), Partner München-Neuherberg, Neuherberg, Germany
| | - Barbara Thorand
- Institute of Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), Neuherberg, Germany.
- Institute for Medical Information Processing, Biometry and Epidemiology (IBE), Faculty of Medicine, Pettenkofer School of Public Health, LMU Munich, Munich, Germany.
- German Center for Diabetes Research (DZD), Partner München-Neuherberg, Neuherberg, Germany.
| |
Collapse
|
21
|
Petrie MA, Suneja M, Shields RK. Distinct Genomic Expression Signatures after Low-Force Electrically Induced Exercises in Persons with Spinal Cord Injury. Int J Mol Sci 2024; 25:10189. [PMID: 39337673 PMCID: PMC11432617 DOI: 10.3390/ijms251810189] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2024] [Revised: 09/12/2024] [Accepted: 09/19/2024] [Indexed: 09/30/2024] Open
Abstract
People with a spinal cord injury are at an increased risk of metabolic dysfunction due to skeletal muscle atrophy and the transition of paralyzed muscle to a glycolytic, insulin-resistant phenotype. Providing doses of exercise through electrical muscle stimulation may provide a therapeutic intervention to help restore metabolic function for people with a spinal cord injury, but high-frequency and high-force electrically induced muscle contractions increase fracture risk for the underlying osteoporotic skeletal system. Therefore, we investigated the acute molecular responses after a session of either a 3 Hz or 1 Hz electrically induced exercise program. Ten people with a complete spinal cord injury completed a 1 h (3 Hz) or 3 h (1 Hz) unilateral electrically induced exercise session prior to a skeletal muscle biopsy of the vastus lateralis. The number of pulses was held constant. Tissue samples were analyzed for genomic and epigenomic expression profiles. There was a strong acute response after the 3 Hz exercise leading to the upregulation of early response genes (NR4A3, PGC-1α, ABRA, IRS2, EGR1, ANKRD1, and MYC), which have prominent roles in regulating molecular pathways that control mitochondrial biogenesis, contractile protein synthesis, and metabolism. Additionally, these genes, and others, contributed to the enrichment of pathways associated with signal transduction, cellular response to stimuli, gene expression, and metabolism. While there were similar trends observed after the 1 Hz exercise, the magnitude of gene expression changes did not reach our significance thresholds, despite a constant number of stimuli delivered. There were also no robust acute changes in muscle methylation after either form of exercise. Taken together, this study supports that a dose of low-force electrically induced exercise for 1 h using a 3 Hz stimulation frequency is suitable to trigger an acute genomic response in people with chronic paralysis, consistent with an expression signature thought to improve the metabolic and contractile phenotype of paralyzed muscle, if performed on a regular basis.
Collapse
Affiliation(s)
- Michael A. Petrie
- Department of Physical Therapy and Rehabilitation Science, Carver College of Medicine, The University of Iowa, Iowa City, IA 52242, USA;
| | - Manish Suneja
- Department of Internal Medicine, Carver College of Medicine, The University of Iowa, Iowa City, IA 52242, USA;
| | - Richard K. Shields
- Department of Physical Therapy and Rehabilitation Science, Carver College of Medicine, The University of Iowa, Iowa City, IA 52242, USA;
| |
Collapse
|
22
|
Huang Y, Li N, Jiang J, Pei Y, Gao S, Qian Y, Xing Y, Zhou T, Lian Y, Shi M. Metabolic reprogramming-related gene classifier distinguishes malignant from the benign pulmonary nodules. Heliyon 2024; 10:e37214. [PMID: 39296187 PMCID: PMC11409088 DOI: 10.1016/j.heliyon.2024.e37214] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2023] [Revised: 07/02/2024] [Accepted: 08/29/2024] [Indexed: 09/21/2024] Open
Abstract
The current existing classifiers for distinguishing malignant from benign pulmonary nodules is limited by effectiveness or clinical practicality. In our study, we aimed to develop and validate a gene classifier for lung cancer diagnosis. To identify the genes involved in this process, we used the weighted gene co-expression network analysis to analyze gene expression datasets from Gene Expression Omnibus (GEO). We identified the three most relevant modules associated with malignant nodules and performed functional enrichment analysis on them. The results indicated significant involvement in metabolic, immune-related, cell cycle, and viral-related processes. All three modules showed enrichment in metabolic reprogramming pathways. Based on these genes, we intersected genes from the three modules with metabolic reprogramming-related genes and further intersected with differentially expressed genes to get 78 genes. After machine learning algorithms and manual selection, we finally got a nine-gene classifier consisting of SEC24D, RPSA, PSME3, PSMD8, PSMB7, NCOA1, MED12, LPCAT1, and AKR1C3. Our developed and validated classifier-based model demonstrated good discrimination, with an area under the curve (AUC) of 0.763 in the development cohort, 0.744 in the internal validation cohort, and 0.718 in the external validation cohort, and outperformed previous clinical models. Moreover, the addition of nodule size improved the predictive capability of the classifier. We further verify the expression of the gene in the classifier using TCGA lung cancer samples and found eight of the genes showed significant differential expression in lung adenocarcinoma while all nine genes showed significant differential expression in lung squamous carcinoma. Our findings underscore the significance of metabolic reprogramming pathways in patients with malignant pulmonary nodules, and our gene classifier can assist clinicians in differentiating benign from malignant pulmonary nodules in clinical settings.
Collapse
Affiliation(s)
- Yongkang Huang
- Department of Respiratory and Critical Care Medicine, the Second Affiliated Hospital of Soochow University, 1055 Sanxiang Road, Suzhou, 215004, Jiangsu, China
| | - Na Li
- Department of Respiratory and Critical Care Medicine, the Fourth Affiliated Hospital of Soochow University, 9 Chongwen Road, Suzhou, 215004, Jiangsu, China
| | - Jie Jiang
- Department of Thoracic Surgery, the Affiliated Brain Hospital of Nanjing Medical University, 264 Guangzhou Road, Nanjing, 210003, Jiangsu, China
| | - Yongjian Pei
- Department of Respiratory and Critical Care Medicine, the Second Affiliated Hospital of Soochow University, 1055 Sanxiang Road, Suzhou, 215004, Jiangsu, China
| | - Shiyuan Gao
- Department of Respiratory and Critical Care Medicine, the Second Affiliated Hospital of Soochow University, 1055 Sanxiang Road, Suzhou, 215004, Jiangsu, China
| | - Yajuan Qian
- Department of Respiratory and Critical Care Medicine, the Second Affiliated Hospital of Soochow University, 1055 Sanxiang Road, Suzhou, 215004, Jiangsu, China
| | - Yufei Xing
- Department of Respiratory and Critical Care Medicine, the Second Affiliated Hospital of Soochow University, 1055 Sanxiang Road, Suzhou, 215004, Jiangsu, China
| | - Tong Zhou
- Department of Respiratory and Critical Care Medicine, the Second Affiliated Hospital of Soochow University, 1055 Sanxiang Road, Suzhou, 215004, Jiangsu, China
| | - Yixin Lian
- Department of Respiratory and Critical Care Medicine, the Second Affiliated Hospital of Soochow University, 1055 Sanxiang Road, Suzhou, 215004, Jiangsu, China
| | - Minhua Shi
- Department of Respiratory and Critical Care Medicine, the Second Affiliated Hospital of Soochow University, 1055 Sanxiang Road, Suzhou, 215004, Jiangsu, China
| |
Collapse
|
23
|
Echeverría-Garcés G, Ramos-Medina MJ, González A, Vargas R, Cabrera-Andrade A, Armendáriz-Castillo I, García-Cárdenas JM, Ramírez-Sánchez D, Altamirano-Colina A, Echeverría-Espinoza P, Freire MP, Ocaña-Paredes B, Rivera-Orellana S, Guerrero S, Quiñones LA, López-Cortés A. Worldwide analysis of actionable genomic alterations in lung cancer and targeted pharmacogenomic strategies. Heliyon 2024; 10:e37488. [PMID: 39296198 PMCID: PMC11409134 DOI: 10.1016/j.heliyon.2024.e37488] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2024] [Revised: 08/29/2024] [Accepted: 09/04/2024] [Indexed: 09/21/2024] Open
Abstract
Based on data from the Global Cancer Statistics 2022, lung cancer stands as the most lethal cancer worldwide, with age-adjusted incidence and mortality rates of 23.6 and 16.9 per 100,000 people, respectively. Despite significant strides in precision oncology driven by large-scale international research consortia, there remains a critical need to deepen our understanding of the genomic landscape across diverse racial and ethnic groups. To address this challenge, we performed comprehensive in silico analyses and data mining to identify pathogenic variants in genes that drive lung cancer. We subsequently calculated the allele frequencies and assessed the deleteriousness of these oncogenic variants among populations such as African, Amish, Ashkenazi Jewish, East and South Asian, Finnish and non-Finnish European, Latino, and Middle Eastern. Our analysis examined 117,707 variants within 86 lung cancer-associated genes across 75,109 human genomes, uncovering 8042 variants that are known or predicted to be pathogenic. We prioritized variants based on their allele frequencies and deleterious scores, and identified those with potential significance for response to anti-cancer therapies through in silico drug simulations, current clinical pharmacogenomic guidelines, and ongoing late-stage clinical trials targeting lung cancer-driving proteins. In conclusion, it is crucial to unite global efforts to create public health policies that emphasize prevention strategies and ensure access to clinical trials, pharmacogenomic testing, and cancer research for these groups in developed nations.
Collapse
Affiliation(s)
- Gabriela Echeverría-Garcés
- Centro de Referencia Nacional de Genómica, Secuenciación y Bioinformática, Instituto Nacional de Investigación en Salud Pública "Leopoldo Izquieta Pérez", Quito, Ecuador
- Latin American Network for the Implementation and Validation of Clinical Pharmacogenomics Guidelines (RELIVAF-CYTED), Santiago, Chile
| | - María José Ramos-Medina
- German Cancer Research Center (DKFZ), Faculty of Biosciences, Heidelberg University, Heidelberg, Germany
| | - Ariana González
- Latin American Network for the Implementation and Validation of Clinical Pharmacogenomics Guidelines (RELIVAF-CYTED), Santiago, Chile
- Dasa Genómica Latam, Buenos Aires, Argentina
| | - Rodrigo Vargas
- Latin American Network for the Implementation and Validation of Clinical Pharmacogenomics Guidelines (RELIVAF-CYTED), Santiago, Chile
- Department of Molecular Biology, Galileo University, Guatemala City, Guatemala
| | - Alejandro Cabrera-Andrade
- Escuela de Enfermería, Facultad de Ciencias de la Salud, Universidad de Las Américas, Quito, Ecuador
- Grupo de Bio-Quimioinformática, Universidad de Las Américas, Quito, Ecuador
| | - Isaac Armendáriz-Castillo
- Latin American Network for the Implementation and Validation of Clinical Pharmacogenomics Guidelines (RELIVAF-CYTED), Santiago, Chile
| | - Jennyfer M García-Cárdenas
- Latin American Network for the Implementation and Validation of Clinical Pharmacogenomics Guidelines (RELIVAF-CYTED), Santiago, Chile
- Laboratorio de Ciencia de Datos Biomédicos, Escuela de Medicina, Facultad de Ciencias Médicas de la Salud y de la Vida, Universidad Internacional del Ecuador, Quito, Ecuador
| | - David Ramírez-Sánchez
- Cancer Research Group (CRG), Faculty of Medicine, Universidad de Las Américas, Quito, Ecuador
| | | | | | - María Paula Freire
- Cancer Research Group (CRG), Faculty of Medicine, Universidad de Las Américas, Quito, Ecuador
| | - Belén Ocaña-Paredes
- Cancer Research Group (CRG), Faculty of Medicine, Universidad de Las Américas, Quito, Ecuador
| | | | - Santiago Guerrero
- Latin American Network for the Implementation and Validation of Clinical Pharmacogenomics Guidelines (RELIVAF-CYTED), Santiago, Chile
- Laboratorio de Ciencia de Datos Biomédicos, Escuela de Medicina, Facultad de Ciencias Médicas de la Salud y de la Vida, Universidad Internacional del Ecuador, Quito, Ecuador
| | - Luis A Quiñones
- Latin American Network for the Implementation and Validation of Clinical Pharmacogenomics Guidelines (RELIVAF-CYTED), Santiago, Chile
- Laboratory of Chemical Carcinogenesis and Pharmacogenetics, Department of Basic-Clinical Oncology (DOBC), Faculty of Medicine, University of Chile, Santiago, Chile
- Department of Pharmaceutical Sciences and Technology, Faculty of Chemical and Pharmaceutical Sciences, University of Chile, Santiago, Chile
| | - Andrés López-Cortés
- Cancer Research Group (CRG), Faculty of Medicine, Universidad de Las Américas, Quito, Ecuador
| |
Collapse
|
24
|
Sung CC, Luxton GWG, Hung KS, Wu YF, Wang CC, Hsu CS, Hu CF. Whole exome sequencing identifies genetic markers of enterovirus susceptibility in East Asians. Front Microbiol 2024; 15:1452595. [PMID: 39234544 PMCID: PMC11372244 DOI: 10.3389/fmicb.2024.1452595] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2024] [Accepted: 07/29/2024] [Indexed: 09/06/2024] Open
Abstract
Introduction Following acute enterovirus (EV) infection, outcomes vary based on factors like the immune response, viral cell entry receptor expression levels, tissue tropism, and genetic factors of both the host and virus. While most individuals exhibit mild, self-limited symptoms, others may suffer severe complications or prolonged infections that can lead to autoimmune disorders. Methods To elucidate host responses to EV infection, we performed whole exome sequencing on blood samples from both infected and uninfected individuals. Our initial focus was on genes encoding EV entry receptors-PSGL-1, SCARB2, and ANAXA2 for EV-A71, and CD155 for poliovirus-and on host genes ACBD3 and PI4KΒ, crucial for EV replication. Results Although no specific genetic variants directly associated with EV infection were identified, we discovered 118 variants across 116 genes enriched in East Asian populations through multi-layered variant filtering. These variants were further analyzed for their potential impacts on organs, biological processes, and molecular pathways. Phenome-wide association studies were conducted to refine our understanding of their contributions to EV infection susceptibility. Discussion Our findings aim to develop a predictive panel based on these 118 variants, which could help susceptible individuals during EV outbreaks, guiding targeted clinical interventions and preventative strategies.
Collapse
Affiliation(s)
- Chia-Cheng Sung
- Department of Pediatrics, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
| | - G W Gant Luxton
- Department of Molecular and Cellular Biology, University of California, Davis, Davis, CA, United States
| | - Kuo-Sheng Hung
- Center for Precision Medicine and Genomics, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
| | - Yung-Fu Wu
- Center for Precision Medicine and Genomics, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
| | - Chih-Chien Wang
- Department of Pediatrics, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
| | - Chih-Sin Hsu
- Genomics Center for Clinical and Biotechnological Applications, Cancer Progression Research Center, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Chih-Fen Hu
- Department of Pediatrics, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
| |
Collapse
|
25
|
López-Cortés A, Cabrera-Andrade A, Echeverría-Garcés G, Echeverría-Espinoza P, Pineda-Albán M, Elsitdie N, Bueno-Miño J, Cruz-Segundo CM, Dorado J, Pazos A, Gonzáles-Díaz H, Pérez-Castillo Y, Tejera E, Munteanu CR. Unraveling druggable cancer-driving proteins and targeted drugs using artificial intelligence and multi-omics analyses. Sci Rep 2024; 14:19359. [PMID: 39169044 PMCID: PMC11339426 DOI: 10.1038/s41598-024-68565-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2024] [Accepted: 07/25/2024] [Indexed: 08/23/2024] Open
Abstract
The druggable proteome refers to proteins that can bind to small molecules with appropriate chemical affinity, inducing a favorable clinical response. Predicting druggable proteins through screening and in silico modeling is imperative for drug design. To contribute to this field, we developed an accurate predictive classifier for druggable cancer-driving proteins using amino acid composition descriptors of protein sequences and 13 machine learning linear and non-linear classifiers. The optimal classifier was achieved with the support vector machine method, utilizing 200 tri-amino acid composition descriptors. The high performance of the model is evident from an area under the receiver operating characteristics (AUROC) of 0.975 ± 0.003 and an accuracy of 0.929 ± 0.006 (threefold cross-validation). The machine learning prediction model was enhanced with multi-omics approaches, including the target-disease evidence score, the shortest pathways to cancer hallmarks, structure-based ligandability assessment, unfavorable prognostic protein analysis, and the oncogenic variome. Additionally, we performed a drug repurposing analysis to identify drugs with the highest affinity capable of targeting the best predicted proteins. As a result, we identified 79 key druggable cancer-driving proteins with the highest ligandability, and 23 of them demonstrated unfavorable prognostic significance across 16 TCGA PanCancer types: CDKN2A, BCL10, ACVR1, CASP8, JAG1, TSC1, NBN, PREX2, PPP2R1A, DNM2, VAV1, ASXL1, TPR, HRAS, BUB1B, ATG7, MARK3, SETD2, CCNE1, MUTYH, CDKN2C, RB1, and SMARCA4. Moreover, we prioritized 11 clinically relevant drugs targeting these proteins. This strategy effectively predicts and prioritizes biomarkers, therapeutic targets, and drugs for in-depth studies in clinical trials. Scripts are available at https://github.com/muntisa/machine-learning-for-druggable-proteins .
Collapse
Affiliation(s)
- Andrés López-Cortés
- Cancer Research Group (CRG), Faculty of Medicine, Universidad de Las Américas, Quito, Ecuador.
| | - Alejandro Cabrera-Andrade
- Grupo de Bio-Quimioinformática, Universidad de Las Américas, Quito, Ecuador
- Escuela de Enfermería, Facultad de Ciencias de la Salud, Universidad de Las Américas, Quito, Ecuador
| | - Gabriela Echeverría-Garcés
- Centro de Referencia Nacional de Genómica, Secuenciación y Bioinformática, Instituto Nacional de Investigación en Salud Pública "Leopoldo Izquieta Pérez", Quito, Ecuador
- Latin American Network for the Implementation and Validation of Clinical Pharmacogenomics Guidelines (RELIVAF-CYTED), Santiago, Chile
| | | | - Micaela Pineda-Albán
- Cancer Research Group (CRG), Faculty of Medicine, Universidad de Las Américas, Quito, Ecuador
| | - Nicole Elsitdie
- Cancer Research Group (CRG), Faculty of Medicine, Universidad de Las Américas, Quito, Ecuador
| | - José Bueno-Miño
- Cancer Research Group (CRG), Faculty of Medicine, Universidad de Las Américas, Quito, Ecuador
| | - Carlos M Cruz-Segundo
- RNASA-IMEDIR, Computer Science Faculty, University of A Coruna, A Coruña, Spain
- Tecnológico de Estudios Superiores de Jocotitlán, Jocotitlán, Mexico
| | - Julian Dorado
- RNASA-IMEDIR, Computer Science Faculty, University of A Coruna, A Coruña, Spain
- Centro de Investigación en Tecnologías de la Información y las Comunicaciones (CITIC), University of A Coruna, A Coruña, Spain
| | - Alejandro Pazos
- RNASA-IMEDIR, Computer Science Faculty, University of A Coruna, A Coruña, Spain
- Centro de Investigación en Tecnologías de la Información y las Comunicaciones (CITIC), University of A Coruna, A Coruña, Spain
- Biomedical Research Institute of A Coruna (INIBIC), University Hospital Complex of A Coruna (CHUAC), A Coruña, Spain
| | - Humberto Gonzáles-Díaz
- Department of Organic Chemistry II, University of the Basque Country UPV/EHU, Biscay, Spain
- IKERBASQUE, Basque Foundation for Science, Biscay, Spain
| | | | - Eduardo Tejera
- Grupo de Bio-Quimioinformática, Universidad de Las Américas, Quito, Ecuador
| | - Cristian R Munteanu
- RNASA-IMEDIR, Computer Science Faculty, University of A Coruna, A Coruña, Spain
- Centro de Investigación en Tecnologías de la Información y las Comunicaciones (CITIC), University of A Coruna, A Coruña, Spain
- Biomedical Research Institute of A Coruna (INIBIC), University Hospital Complex of A Coruna (CHUAC), A Coruña, Spain
| |
Collapse
|
26
|
Wang F, Chen L, Nie M, Li Z. Integrative analysis of causal associations between neurodegenerative diseases and colorectal cancer. Heliyon 2024; 10:e35432. [PMID: 39170445 PMCID: PMC11336615 DOI: 10.1016/j.heliyon.2024.e35432] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2024] [Revised: 07/24/2024] [Accepted: 07/29/2024] [Indexed: 08/23/2024] Open
Abstract
Background Observational studies have shown that the correlation between neurodegenerative diseases and colorectal cancer (CRC) remains controversial. Therefore, this study aimed to verify the causal association between these two diseases. Methods Mendelian randomization (MR) analysis was used to assess the causal relationships between five major neurodegenerative diseases and CRC. Multivariable MR (MVMR) analysis was conducted to assess the direct causal effect of neurodegenerative diseases on CRC. Colocalization and pathway enrichment analyses were conducted to further elucidate our results. Sensitivity analysis was conducted to assess the robustness of the results. Results Genetically predicted Alzheimer's disease (AD) nominally increased CRC risk (OR = 1.0620, 95%CI = 1.0127-1.1136, P = 0.013). There was no causal effect of genetically predicted CRC on neurodegenerative diseases. Furthermore, we demonstrated that genetically predicted AD marginally increased colon cancer risk (OR = 1.1621, 95%CI = 1.0267-1.3153, P = 0.017). Genetically predicted Lewy body dementia (LBD) had a significant causal effect on the increasing risk of colon cancer (IVW OR = 1.1779, 95%CI = 1.0694-1.2975, P = 0.001). MVMR indicated that effect of AD on colon cancer was driven by LBD, type 2 diabetes, body mass index, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, triglyceride, total cholesterol (TC), processed meat consumption, smoking, alcohol consumption, and educational attainment, whereas the effect of LBD on colon cancer was only influenced by TC. Colocalization and pathway enrichment analysis suggested that LBD and colon cancer possibly shared causal variants (nearby gene APOE), and ERBB4 signaling and lipid metabolism may mediate the causal association between LBD and colon cancer. Sensitivity analysis confirmed the reliability of our findings. Conclusions Our study demonstrated that genetic vulnerabilities to AD nominally increased the overall risk of CRC and colon cancer. Genetically predicted LBD indicated an elevated risk of colon cancer, potentially linked to ERBB4 signaling and lipid metabolism.
Collapse
Affiliation(s)
- Feifan Wang
- Gastrointestinal Disease Diagnosis and Treatment Center, The First Hospital of Hebei Medical University, Shijiazhuang, 050000, China
| | - Lu Chen
- Department of Medical Oncology and Radiation Sickness, Peking University Third Hospital, Beijing, 100191, China
| | - Mengke Nie
- Department of General Practice, Huaihe Hospital of Henan University, Kaifeng, 475000, China
| | - Zhongxin Li
- Gastrointestinal Disease Diagnosis and Treatment Center, The First Hospital of Hebei Medical University, Shijiazhuang, 050000, China
| |
Collapse
|
27
|
Li Y, Jiang LN, Zhao BK, Li ML, Jiang YY, Liu YS, Liu SH, Zhu L, Ye X, Zhao JM. Lecithin-cholesterol acyltransferase is a potential tumor suppressor and predictive marker for hepatocellular carcinoma metastasis. World J Gastrointest Oncol 2024; 16:3651-3671. [PMID: 39171187 PMCID: PMC11334038 DOI: 10.4251/wjgo.v16.i8.3651] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/24/2024] [Revised: 05/27/2024] [Accepted: 06/18/2024] [Indexed: 08/07/2024] Open
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) is a major cause of cancer mortality worldwide, and metastasis is the main cause of early recurrence and poor prognosis. However, the mechanism of metastasis remains poorly understood. AIM To determine the possible mechanism affecting HCC metastasis and provide a possible theoretical basis for HCC treatment. METHODS The candidate molecule lecithin-cholesterol acyltransferase (LCAT) was screened by gene microarray and bioinformatics analysis. The expression levels of LCAT in clinical cohort samples was detected by quantitative real-time polymerase chain reaction and western blotting. The proliferation, migration, invasion and tumor-forming ability were measured by Cell Counting Kit-8, Transwell cell migration, invasion, and clonal formation assays, respectively. Tumor formation was detected in nude mice after LCAT gene knockdown or overexpression. The immunohistochemistry for Ki67, E-cadherin, N-cadherin, matrix metalloproteinase 9 and vascular endothelial growth factor were performed in liver tissues to assess the effect of LCAT on HCC. Gene set enrichment analysis (GSEA) on various gene signatures were analyzed with GSEA version 3.0. Three machine-learning algorithms (random forest, support vector machine, and logistic regression) were applied to predict HCC metastasis in The Cancer Genome Atlas and GEO databases. RESULTS LCAT was identified as a novel gene relating to HCC metastasis by using gene microarray in HCC tissues. LCAT was significantly downregulated in HCC tissues, which is correlated with recurrence, metastasis and poor outcome of HCC patients. Functional analysis indicated that LCAT inhibited HCC cell proliferation, migration and invasion both in vitro and in vivo. Clinicopathological data showed that LCAT was negatively associated with HCC size and metastasis (HCC size ≤ 3 cm vs 3-9 cm, P < 0.001; 3-9 cm vs > 9 cm, P < 0.01; metastatic-free HCC vs extrahepatic metastatic HCC, P < 0.05). LCAT suppressed the growth, migration and invasion of HCC cell lines via PI3K/AKT/mTOR signaling. Our results indicated that the logistic regression model based on LCAT, TNM stage and the serum level of α-fetoprotein in HCC patients could effectively predict high metastatic risk HCC patients. CONCLUSION LCAT is downregulated at translational and protein levels in HCC and might inhibit tumor metastasis via attenuating PI3K/AKT/mTOR signaling. LCAT is a prognostic marker and potential therapeutic target for HCC.
Collapse
Affiliation(s)
- Yan Li
- Department of Pathology and Hepatology, The Fifth Medical Center of Chinese PLA General Hospital, Beijing 100039, China
| | - Li-Na Jiang
- Department of Pathology and Hepatology, The Fifth Medical Center of Chinese PLA General Hospital, Beijing 100039, China
| | - Bo-Kang Zhao
- Department of Hepatology, Center of Infectious Diseases and Pathogen Biology, The First Hospital of Jilin University, Changchun 130061, Jilin Province, China
| | - Mei-Ling Li
- Department of Pathology and Hepatology, The Fifth Medical Center of Chinese PLA General Hospital, Beijing 100039, China
| | - Yi-Yun Jiang
- Department of Pathology and Hepatology, The Fifth Medical Center of Chinese PLA General Hospital, Beijing 100039, China
| | - Yi-Si Liu
- First Department of Liver Disease Center, Beijing Youan Hospital, Capital Medical University, Beijing 100069, China
| | - Shu-Hong Liu
- Department of Pathology and Hepatology, The Fifth Medical Center of Chinese PLA General Hospital, Beijing 100039, China
| | - Li Zhu
- Department of Pathology and Hepatology, The Fifth Medical Center of Chinese PLA General Hospital, Beijing 100039, China
| | - Xin Ye
- Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China
- Savaid Medical School, University of Chinese Academy of Sciences, Beijing 100190, China
| | - Jing-Min Zhao
- Department of Pathology, The Fifth Medical Center of Chinese PLA General Hospital, Beijing 100039, China
| |
Collapse
|
28
|
Ibrahim H, Balboa D, Saarimäki-Vire J, Montaser H, Dyachok O, Lund PE, Omar-Hmeadi M, Kvist J, Dwivedi OP, Lithovius V, Barsby T, Chandra V, Eurola S, Ustinov J, Tuomi T, Miettinen PJ, Barg S, Tengholm A, Otonkoski T. RFX6 haploinsufficiency predisposes to diabetes through impaired beta cell function. Diabetologia 2024; 67:1642-1662. [PMID: 38743124 PMCID: PMC11343796 DOI: 10.1007/s00125-024-06163-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/08/2023] [Accepted: 03/21/2024] [Indexed: 05/16/2024]
Abstract
AIMS/HYPOTHESIS Regulatory factor X 6 (RFX6) is crucial for pancreatic endocrine development and differentiation. The RFX6 variant p.His293LeufsTer7 is significantly enriched in the Finnish population, with almost 1:250 individuals as a carrier. Importantly, the FinnGen study indicates a high predisposition for heterozygous carriers to develop type 2 and gestational diabetes. However, the precise mechanism of this predisposition remains unknown. METHODS To understand the role of this variant in beta cell development and function, we used CRISPR technology to generate allelic series of pluripotent stem cells. We created two isogenic stem cell models: a human embryonic stem cell model; and a patient-derived stem cell model. Both were differentiated into pancreatic islet lineages (stem-cell-derived islets, SC-islets), followed by implantation in immunocompromised NOD-SCID-Gamma mice. RESULTS Stem cell models of the homozygous variant RFX6-/- predictably failed to generate insulin-secreting pancreatic beta cells, mirroring the phenotype observed in Mitchell-Riley syndrome. Notably, at the pancreatic endocrine stage, there was an upregulation of precursor markers NEUROG3 and SOX9, accompanied by increased apoptosis. Intriguingly, heterozygous RFX6+/- SC-islets exhibited RFX6 haploinsufficiency (54.2% reduction in protein expression), associated with reduced beta cell maturation markers, altered calcium signalling and impaired insulin secretion (62% and 54% reduction in basal and high glucose conditions, respectively). However, RFX6 haploinsufficiency did not have an impact on beta cell number or insulin content. The reduced insulin secretion persisted after in vivo implantation in mice, aligning with the increased risk of variant carriers to develop diabetes. CONCLUSIONS/INTERPRETATION Our allelic series isogenic SC-islet models represent a powerful tool to elucidate specific aetiologies of diabetes in humans, enabling the sensitive detection of aberrations in both beta cell development and function. We highlight the critical role of RFX6 in augmenting and maintaining the pancreatic progenitor pool, with an endocrine roadblock and increased cell death upon its loss. We demonstrate that RFX6 haploinsufficiency does not affect beta cell number or insulin content but does impair function, predisposing heterozygous carriers of loss-of-function variants to diabetes. DATA AVAILABILITY Ultra-deep bulk RNA-seq data for pancreatic differentiation stages 3, 5 and 7 of H1 RFX6 genotypes are deposited in the Gene Expression Omnibus database with accession code GSE234289. Original western blot images are deposited at Mendeley ( https://data.mendeley.com/datasets/g75drr3mgw/2 ).
Collapse
Affiliation(s)
- Hazem Ibrahim
- Stem Cells and Metabolism Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
| | - Diego Balboa
- Stem Cells and Metabolism Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland
| | - Jonna Saarimäki-Vire
- Stem Cells and Metabolism Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland
| | - Hossam Montaser
- Stem Cells and Metabolism Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland
| | - Oleg Dyachok
- Department of Medical Cell Biology, Uppsala University, Uppsala, Sweden
| | - Per-Eric Lund
- Department of Medical Cell Biology, Uppsala University, Uppsala, Sweden
| | | | - Jouni Kvist
- Stem Cells and Metabolism Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland
| | - Om P Dwivedi
- Institute for Molecular Medicine Finland, FIMM, HiLIFE, Helsinki, Finland
- Research Program of Clinical and Molecular Metabolism, University of Helsinki, Helsinki, Finland
| | - Väinö Lithovius
- Stem Cells and Metabolism Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland
| | - Tom Barsby
- Stem Cells and Metabolism Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland
| | - Vikash Chandra
- Stem Cells and Metabolism Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland
| | - Solja Eurola
- Stem Cells and Metabolism Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland
| | - Jarkko Ustinov
- Stem Cells and Metabolism Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland
| | - Tiinamaija Tuomi
- Institute for Molecular Medicine Finland, FIMM, HiLIFE, Helsinki, Finland
- Research Program of Clinical and Molecular Metabolism, University of Helsinki, Helsinki, Finland
- Folkhälsan Institute of Genetics, Folkhälsan Research Center, Biomedicum Helsinki, Finland
- Abdominal Center, Endocrinology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
- Lund University Diabetes Centre, Department of Clinical Sciences, Lund University, Lund, Sweden
| | - Päivi J Miettinen
- Department of Pediatrics, Helsinki University Hospital, Helsinki, Finland
| | - Sebastian Barg
- Department of Medical Cell Biology, Uppsala University, Uppsala, Sweden
| | - Anders Tengholm
- Department of Medical Cell Biology, Uppsala University, Uppsala, Sweden
| | - Timo Otonkoski
- Stem Cells and Metabolism Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
- Department of Pediatrics, Helsinki University Hospital, Helsinki, Finland.
| |
Collapse
|
29
|
Nandanwar N, Gibson JE, Neely MN. Transcriptome profiles of macrophages upon infection by morphotypic smooth and rough variants of Mycobacterium abscessus. Microbes Infect 2024; 26:105367. [PMID: 38782181 DOI: 10.1016/j.micinf.2024.105367] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2024] [Revised: 05/07/2024] [Accepted: 05/17/2024] [Indexed: 05/25/2024]
Abstract
Mycobacterium abscessus (Mab) infection can be deadly in patients with chronic lung diseases like cystic fibrosis (CF). In vitro and in vivo, Mab may adopt a smooth (S) or rough (R) morphotype, the latter linked to more severe disease conditions. In vitro studies revealed differences in pathogenicity and immune response to S and R morphotypes. We propose that in vivo both morphotypes exist and may transiently switch depending on the environment, having important pathogenic and immunologic consequences. This can be modeled by morphotypic S and R variants of Mab selected based on in vitro growth conditions. Here, we report the first analysis of early transcriptional events in mouse bone marrow derived macrophages (BMDMs) upon infection with media-selected interchangeable Mab-S and Mab-R morphotypes. The early transcriptional events after infection with both morphotypes showed considerable overlap of the pro-inflammatory genes that were differentially regulated compared to the uninfected macrophages. We also observed signature genes significantly differentially regulated in macrophages during infection of media-selected morphotypic Mab-S and Mab-R variants. In conclusion, media-selected Mab-S and Mab-R behave in a similar fashion to stable S and R types with respect to pathogenesis and immune response, serving as a useful model for environmentally influenced morphotype selection.
Collapse
Affiliation(s)
- Nishant Nandanwar
- Division of Infectious Diseases, Department of Pediatrics, Children's Hospital Los Angeles, CA, 90027, USA.
| | - Joy E Gibson
- Division of Infectious Diseases, Department of Pediatrics, Children's Hospital Los Angeles, CA, 90027, USA; Department of Pediatrics, Keck School of Medicine, University of Southern California, Los Angeles, CA, 90027, USA
| | - Michael N Neely
- Division of Infectious Diseases, Department of Pediatrics, Children's Hospital Los Angeles, CA, 90027, USA; Department of Pediatrics, Keck School of Medicine, University of Southern California, Los Angeles, CA, 90027, USA
| |
Collapse
|
30
|
Kashyap MK, Karathia H, Kumar D, Vera Alvarez R, Forero-Forero JV, Moreno E, Lujan JV, Amaya-Chanaga CI, Vidal NM, Yu Z, Ghia EM, Lengerke-Diaz PA, Achinko D, Choi MY, Rassenti LZ, Mariño-Ramírez L, Mount SM, Hannenhalli S, Kipps TJ, Castro JE. Aberrant spliceosome activity via elevated intron retention and upregulation and phosphorylation of SF3B1 in chronic lymphocytic leukemia. MOLECULAR THERAPY. NUCLEIC ACIDS 2024; 35:102202. [PMID: 38846999 PMCID: PMC11154714 DOI: 10.1016/j.omtn.2024.102202] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 07/14/2022] [Accepted: 04/24/2024] [Indexed: 06/09/2024]
Abstract
Splicing factor 3b subunit 1 (SF3B1) is the largest subunit and core component of the spliceosome. Inhibition of SF3B1 was associated with an increase in broad intron retention (IR) on most transcripts, suggesting that IR can be used as a marker of spliceosome inhibition in chronic lymphocytic leukemia (CLL) cells. Furthermore, we separately analyzed exonic and intronic mapped reads on annotated RNA-sequencing transcripts obtained from B cells (n = 98 CLL patients) and healthy volunteers (n = 9). We measured intron/exon ratio to use that as a surrogate for alternative RNA splicing (ARS) and found that 66% of CLL-B cell transcripts had significant IR elevation compared with normal B cells (NBCs) and that correlated with mRNA downregulation and low expression levels. Transcripts with the highest IR levels belonged to biological pathways associated with gene expression and RNA splicing. A >2-fold increase of active pSF3B1 was observed in CLL-B cells compared with NBCs. Additionally, when the CLL-B cells were treated with macrolides (pladienolide-B), a significant decrease in pSF3B1, but not total SF3B1 protein, was observed. These findings suggest that IR/ARS is increased in CLL, which is associated with SF3B1 phosphorylation and susceptibility to SF3B1 inhibitors. These data provide additional support to the relevance of ARS in carcinogenesis and evidence of pSF3B1 participation in this process.
Collapse
Affiliation(s)
- Manoj Kumar Kashyap
- Moores Cancer Center, University of California, San Diego, La Jolla, CA 92093-0820, USA
- Division of Hematology Oncology, Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA
- Amity Stem Cell Institute, Amity Medical School, Amity University Haryana, Panchgaon (Manesar), Gurugram (HR) 122413, India
| | - Hiren Karathia
- Advanced Biomedical Computational Science and National Center for Advancing Translational Sciences, National Cancer Institute, National Institutes of Health, Frederick, MD, USA
- Greenwood Genetic Center, Greenwood, SC, USA
- Center for Bioinformatics and Computational Biology, University of Maryland, College Park, MD 20742, USA
| | - Deepak Kumar
- Moores Cancer Center, University of California, San Diego, La Jolla, CA 92093-0820, USA
| | - Roberto Vera Alvarez
- National Center for Biotechnology Information, National Library of Medicine, National Institutes of Health, Bethesda, MD, USA
| | | | - Eider Moreno
- Department of Internal Medicine, Division of Hematology-Oncology, Mayo Clinic, Phoenix, AZ 85054, USA
| | - Juliana Velez Lujan
- Moores Cancer Center, University of California, San Diego, La Jolla, CA 92093-0820, USA
| | | | - Newton Medeiros Vidal
- National Center for Biotechnology Information, National Library of Medicine, National Institutes of Health, Bethesda, MD, USA
| | - Zhe Yu
- Moores Cancer Center, University of California, San Diego, La Jolla, CA 92093-0820, USA
| | - Emanuela M. Ghia
- Moores Cancer Center, University of California, San Diego, La Jolla, CA 92093-0820, USA
- Division of Hematology Oncology, Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA
- Center for Novel Therapeutics, University of California, San Diego, La Jolla, CA 92037, USA
| | - Paula A. Lengerke-Diaz
- Department of Internal Medicine, Division of Hematology-Oncology, Mayo Clinic, Phoenix, AZ 85054, USA
| | - Daniel Achinko
- National Center for Biotechnology Information, National Library of Medicine, National Institutes of Health, Bethesda, MD, USA
| | - Michael Y. Choi
- Moores Cancer Center, University of California, San Diego, La Jolla, CA 92093-0820, USA
- Division of Hematology Oncology, Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA
- Center for Novel Therapeutics, University of California, San Diego, La Jolla, CA 92037, USA
| | - Laura Z. Rassenti
- Moores Cancer Center, University of California, San Diego, La Jolla, CA 92093-0820, USA
- Division of Hematology Oncology, Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA
- Center for Novel Therapeutics, University of California, San Diego, La Jolla, CA 92037, USA
| | - Leonardo Mariño-Ramírez
- National Center for Biotechnology Information, National Library of Medicine, National Institutes of Health, Bethesda, MD, USA
| | - Stephen M. Mount
- Department of Cell Biology and Molecular Genetics, University of Maryland, College Park, Maryland 20742, USA
| | - Sridhar Hannenhalli
- Cancer Data Science Lab, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Thomas J. Kipps
- Moores Cancer Center, University of California, San Diego, La Jolla, CA 92093-0820, USA
- Division of Hematology Oncology, Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA
- Center for Novel Therapeutics, University of California, San Diego, La Jolla, CA 92037, USA
| | - Januario E. Castro
- Moores Cancer Center, University of California, San Diego, La Jolla, CA 92093-0820, USA
- Department of Internal Medicine, Division of Hematology-Oncology, Mayo Clinic, Phoenix, AZ 85054, USA
| |
Collapse
|
31
|
Chow AK, Low R, Yuan J, Yee KK, Dhaliwal JK, Govia S, Sharmin N. Bioinformatics for Dentistry: A secondary database for the genetics of tooth development. PLoS One 2024; 19:e0303628. [PMID: 38843230 PMCID: PMC11156362 DOI: 10.1371/journal.pone.0303628] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2023] [Accepted: 04/30/2024] [Indexed: 06/09/2024] Open
Abstract
Genes strictly regulate the development of teeth and their surrounding oral structures. Alteration of gene regulation leads to tooth disorders and developmental anomalies in tooth, oral, and facial regions. With the advancement of gene sequencing technology, genomic data is rapidly increasing. However, the large sets of genomic and proteomic data related to tooth development and dental disorders are currently dispersed in many primary databases and literature, making it difficult for users to navigate, extract, study, or analyze. We have curated the scattered genetic data on tooth development and created a knowledgebase called 'Bioinformatics for Dentistry' (https://dentalbioinformatics.com/). This database compiles genomic and proteomic data on human tooth development and developmental anomalies and organizes them according to their roles in different stages of tooth development. The database is built by systemically curating relevant data from the National Library of Medicine (NCBI) GenBank, OMIM: Online Mendelian Inheritance in Man, AlphaFold Protein Structure Database, Reactome pathway knowledgebase, Wiki Pathways, and PubMed. The accuracy of the included data was verified from supporting primary literature. Upon data curation and validation, a simple, easy-to-navigate browser interface was created on WordPress version 6.3.2, with PHP version 8.0. The website is hosted in a cloud hosting service to provide fast and reliable data transfer rate. Plugins are used to ensure the browser's compatibility across different devices. Bioinformatics for Dentistry contains four embedded filters for complex and specific searches and free-text search options for quick and simple searching through the datasets. Bioinformatics for Dentistry is made freely available worldwide, with the hope that this knowledgebase will improve our understanding of the complex genetic regulation of tooth development and will open doors to research initiatives and discoveries. This database will be expanded in the future by incorporating resources and built-in sequence analysis tools, and it will be maintained and updated annually.
Collapse
Affiliation(s)
- Ava K. Chow
- School of Dentistry, College of Health Sciences, Faculty of Medicine & Dentistry, University of Alberta, Edmonton, Canada
| | - Rachel Low
- School of Dentistry, College of Health Sciences, Faculty of Medicine & Dentistry, University of Alberta, Edmonton, Canada
| | - Jerald Yuan
- School of Dentistry, College of Health Sciences, Faculty of Medicine & Dentistry, University of Alberta, Edmonton, Canada
| | - Karen K. Yee
- School of Dentistry, College of Health Sciences, Faculty of Medicine & Dentistry, University of Alberta, Edmonton, Canada
| | - Jaskaranjit Kaur Dhaliwal
- School of Dentistry, College of Health Sciences, Faculty of Medicine & Dentistry, University of Alberta, Edmonton, Canada
| | - Shanice Govia
- School of Dentistry, College of Health Sciences, Faculty of Medicine & Dentistry, University of Alberta, Edmonton, Canada
| | - Nazlee Sharmin
- School of Dentistry, College of Health Sciences, Faculty of Medicine & Dentistry, University of Alberta, Edmonton, Canada
| |
Collapse
|
32
|
Narad P, Kulshrestha S, Chikara A, Gupta V, Kakrania M, Saxena R, Gupta P, Gupta L, Vijayaraghavan P, Sengupta A. Systems-wide analysis of A. fumigatus using kinetic modeling of metabolic pathways to identify putative drug targets. J Biomol Struct Dyn 2024; 42:4379-4394. [PMID: 37334711 DOI: 10.1080/07391102.2023.2223726] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2023] [Accepted: 06/05/2023] [Indexed: 06/20/2023]
Abstract
Aspergillosis is a major causative factor for morbidity in those with impaired immune systems, often caused by Aspergillus fumigatus. The diagnosis and treatment are difficult due to the diversity of individuals and risk factors and still pose a challenge for medical professionals. To understand the pathogenicity of any organism, it is critical to identify the significant metabolic pathways that are involved. Our work focused on developing kinetic models of critical pathways crucial for the survival of A. fumigatus using COPASI. While focusing on the folate biosynthesis, ergosterol biosynthesis and glycolytic pathway; sensitivity, time-course and steady-state analysis were performed to find the proteins/enzymes that are essential in the pathway and can be considered as potential drug targets. For further analysis of the interaction of drug targets identified, a protein-protein interaction (PPI) network was built, and hub nodes were identified using the Cytohubba package from Cytoscape. Based on the findings, dihydropteroate-synthase, dihydrofolate-reductase, 4-amino-4-deoxychorismate synthase, HMG-CoA-reductase, PG-isomerase and hexokinase could act as potential drug targets. Further, molecular docking and MM-GBSA analysis were performed with ligands chosen from DrugBank, and PubChem, and validated by experimental evidence and existing literature based on results from kinetic modeling and PPI network analysis. Based on docking scores and MM-GBSA results, molecular simulations were carried out for 1AJ2-dapsone, 1DIS-sulfamethazine, 1T02-lovastatin and 70YL-3-bromopyruvic acid complexes, which validated our findings. Our study provides a deeper insight into the mechanisms of A. fumigatus's metabolism to reveal dapsone, sulfamethazine, lovastatin and 3-bromopyruvic acid as potential drugs for the treatment of Aspergillosis.
Collapse
Affiliation(s)
- Priyanka Narad
- Systems Biology and Data Analytics Research Lab, Amity Institute of Biotechnology, Amity University Uttar Pradesh, Noida, India
| | - Sudeepti Kulshrestha
- Systems Biology and Data Analytics Research Lab, Amity Institute of Biotechnology, Amity University Uttar Pradesh, Noida, India
| | - Aryan Chikara
- Systems Biology and Data Analytics Research Lab, Amity Institute of Biotechnology, Amity University Uttar Pradesh, Noida, India
| | - Vinayak Gupta
- Systems Biology and Data Analytics Research Lab, Amity Institute of Biotechnology, Amity University Uttar Pradesh, Noida, India
| | - Mahi Kakrania
- Systems Biology and Data Analytics Research Lab, Amity Institute of Biotechnology, Amity University Uttar Pradesh, Noida, India
| | - Ritika Saxena
- Systems Biology and Data Analytics Research Lab, Amity Institute of Biotechnology, Amity University Uttar Pradesh, Noida, India
| | - Payal Gupta
- Systems Biology and Data Analytics Research Lab, Amity Institute of Biotechnology, Amity University Uttar Pradesh, Noida, India
| | - Lovely Gupta
- Anti-mycotic Drug Susceptibility Laboratory, Amity Institute of Biotechnology, Amity University, Noida, India
| | - Pooja Vijayaraghavan
- Anti-mycotic Drug Susceptibility Laboratory, Amity Institute of Biotechnology, Amity University, Noida, India
| | - Abhishek Sengupta
- Systems Biology and Data Analytics Research Lab, Amity Institute of Biotechnology, Amity University Uttar Pradesh, Noida, India
| |
Collapse
|
33
|
Doria-Belenguer S, Xenos A, Ceddia G, Malod-Dognin N, Pržulj N. The axes of biology: a novel axes-based network embedding paradigm to decipher the functional mechanisms of the cell. BIOINFORMATICS ADVANCES 2024; 4:vbae075. [PMID: 38827411 PMCID: PMC11142626 DOI: 10.1093/bioadv/vbae075] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 10/17/2023] [Revised: 04/15/2024] [Accepted: 05/22/2024] [Indexed: 06/04/2024]
Abstract
Summary Common approaches for deciphering biological networks involve network embedding algorithms. These approaches strictly focus on clustering the genes' embedding vectors and interpreting such clusters to reveal the hidden information of the networks. However, the difficulty in interpreting the genes' clusters and the limitations of the functional annotations' resources hinder the identification of the currently unknown cell's functioning mechanisms. We propose a new approach that shifts this functional exploration from the embedding vectors of genes in space to the axes of the space itself. Our methodology better disentangles biological information from the embedding space than the classic gene-centric approach. Moreover, it uncovers new data-driven functional interactions that are unregistered in the functional ontologies, but biologically coherent. Furthermore, we exploit these interactions to define new higher-level annotations that we term Axes-Specific Functional Annotations and validate them through literature curation. Finally, we leverage our methodology to discover evolutionary connections between cellular functions and the evolution of species. Availability and implementation Data and source code can be accessed at https://gitlab.bsc.es/sdoria/axes-of-biology.git.
Collapse
Affiliation(s)
| | | | - Gaia Ceddia
- Barcelona Supercomputing Center (BSC), Barcelona 08034, Spain
| | | | - Nataša Pržulj
- Barcelona Supercomputing Center (BSC), Barcelona 08034, Spain
- Department of Computer Science, University College London, London, WC1E 6BT, United Kingdom
- ICREA, Barcelona 08010, Spain
| |
Collapse
|
34
|
Gupta T, Antanaviciute A, Hyun-Jung Lee C, Ottakandathil Babu R, Aulicino A, Christoforidou Z, Siejka-Zielinska P, O'Brien-Ball C, Chen H, Fawkner-Corbett D, Geros AS, Bridges E, McGregor C, Cianci N, Fryer E, Alham NK, Jagielowicz M, Santos AM, Fellermeyer M, Davis SJ, Parikh K, Cheung V, Al-Hillawi L, Sasson S, Slevin S, Brain O, Fernandes RA, Koohy H, Simmons A. Tracking in situ checkpoint inhibitor-bound target T cells in patients with checkpoint-induced colitis. Cancer Cell 2024; 42:797-814.e15. [PMID: 38744246 DOI: 10.1016/j.ccell.2024.04.010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/23/2023] [Revised: 02/09/2024] [Accepted: 04/17/2024] [Indexed: 05/16/2024]
Abstract
The success of checkpoint inhibitors (CPIs) for cancer has been tempered by immune-related adverse effects including colitis. CPI-induced colitis is hallmarked by expansion of resident mucosal IFNγ cytotoxic CD8+ T cells, but how these arise is unclear. Here, we track CPI-bound T cells in intestinal tissue using multimodal single-cell and subcellular spatial transcriptomics (ST). Target occupancy was increased in inflamed tissue, with drug-bound T cells located in distinct microdomains distinguished by specific intercellular signaling and transcriptional gradients. CPI-bound cells were largely CD4+ T cells, including enrichment in CPI-bound peripheral helper, follicular helper, and regulatory T cells. IFNγ CD8+ T cells emerged from both tissue-resident memory (TRM) and peripheral populations, displayed more restricted target occupancy profiles, and co-localized with damaged epithelial microdomains lacking effective regulatory cues. Our multimodal analysis identifies causal pathways and constitutes a resource to inform novel preventive strategies.
Collapse
Affiliation(s)
- Tarun Gupta
- Medical Research Council (MRC) Translational Immune Discovery Unit, MRC Weatherall Institute of Molecular Medicine (WIMM), Radcliffe Department of Medicine, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DS, UK; Translational Gastroenterology Unit, John Radcliffe Hospital, Oxford OX3 9DU, UK
| | - Agne Antanaviciute
- Medical Research Council (MRC) Translational Immune Discovery Unit, MRC Weatherall Institute of Molecular Medicine (WIMM), Radcliffe Department of Medicine, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DS, UK; MRC WIMM Centre For Computational Biology, MRC Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DS, UK.
| | - Chloe Hyun-Jung Lee
- Medical Research Council (MRC) Translational Immune Discovery Unit, MRC Weatherall Institute of Molecular Medicine (WIMM), Radcliffe Department of Medicine, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DS, UK; MRC WIMM Centre For Computational Biology, MRC Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DS, UK
| | - Rosana Ottakandathil Babu
- Medical Research Council (MRC) Translational Immune Discovery Unit, MRC Weatherall Institute of Molecular Medicine (WIMM), Radcliffe Department of Medicine, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DS, UK; MRC WIMM Centre For Computational Biology, MRC Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DS, UK
| | - Anna Aulicino
- Medical Research Council (MRC) Translational Immune Discovery Unit, MRC Weatherall Institute of Molecular Medicine (WIMM), Radcliffe Department of Medicine, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DS, UK
| | - Zoe Christoforidou
- Medical Research Council (MRC) Translational Immune Discovery Unit, MRC Weatherall Institute of Molecular Medicine (WIMM), Radcliffe Department of Medicine, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DS, UK
| | - Paulina Siejka-Zielinska
- Medical Research Council (MRC) Translational Immune Discovery Unit, MRC Weatherall Institute of Molecular Medicine (WIMM), Radcliffe Department of Medicine, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DS, UK
| | - Caitlin O'Brien-Ball
- Chinese Academy of Medical Sciences (CAMS) Oxford Institute (COI), University of Oxford, Oxford OX3 7BN, UK
| | - Hannah Chen
- Medical Research Council (MRC) Translational Immune Discovery Unit, MRC Weatherall Institute of Molecular Medicine (WIMM), Radcliffe Department of Medicine, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DS, UK
| | - David Fawkner-Corbett
- Medical Research Council (MRC) Translational Immune Discovery Unit, MRC Weatherall Institute of Molecular Medicine (WIMM), Radcliffe Department of Medicine, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DS, UK; Academic Paediatric Surgery Unit (APSU), Nuffield Department of Surgical Sciences, University of Oxford, Oxford OX3 9DU, UK
| | - Ana Sousa Geros
- Medical Research Council (MRC) Translational Immune Discovery Unit, MRC Weatherall Institute of Molecular Medicine (WIMM), Radcliffe Department of Medicine, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DS, UK
| | - Esther Bridges
- Medical Research Council (MRC) Translational Immune Discovery Unit, MRC Weatherall Institute of Molecular Medicine (WIMM), Radcliffe Department of Medicine, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DS, UK
| | - Colleen McGregor
- Medical Research Council (MRC) Translational Immune Discovery Unit, MRC Weatherall Institute of Molecular Medicine (WIMM), Radcliffe Department of Medicine, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DS, UK; Translational Gastroenterology Unit, John Radcliffe Hospital, Oxford OX3 9DU, UK
| | - Nicole Cianci
- Medical Research Council (MRC) Translational Immune Discovery Unit, MRC Weatherall Institute of Molecular Medicine (WIMM), Radcliffe Department of Medicine, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DS, UK; Translational Gastroenterology Unit, John Radcliffe Hospital, Oxford OX3 9DU, UK
| | - Eve Fryer
- Pathology, Department of Cellular Pathology, Oxford University Hospitals NHS Foundation Trust, Oxford OX3 9DU, UK
| | - Nasullah Khalid Alham
- Nuffield Department of Surgical Sciences and Oxford NIHR Biomedical Research Centre (BRC), University of Oxford, John Radcliffe Hospital, Oxford OX3 9DU, UK
| | - Marta Jagielowicz
- Medical Research Council (MRC) Translational Immune Discovery Unit, MRC Weatherall Institute of Molecular Medicine (WIMM), Radcliffe Department of Medicine, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DS, UK
| | - Ana Mafalda Santos
- Medical Research Council (MRC) Translational Immune Discovery Unit, MRC Weatherall Institute of Molecular Medicine (WIMM), Radcliffe Department of Medicine, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DS, UK; Radcliffe Department of Medicine, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DU, UK
| | - Martin Fellermeyer
- Medical Research Council (MRC) Translational Immune Discovery Unit, MRC Weatherall Institute of Molecular Medicine (WIMM), Radcliffe Department of Medicine, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DS, UK; Radcliffe Department of Medicine, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DU, UK
| | - Simon J Davis
- Medical Research Council (MRC) Translational Immune Discovery Unit, MRC Weatherall Institute of Molecular Medicine (WIMM), Radcliffe Department of Medicine, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DS, UK; Radcliffe Department of Medicine, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DU, UK
| | - Kaushal Parikh
- Medical Research Council (MRC) Translational Immune Discovery Unit, MRC Weatherall Institute of Molecular Medicine (WIMM), Radcliffe Department of Medicine, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DS, UK
| | - Vincent Cheung
- Translational Gastroenterology Unit, John Radcliffe Hospital, Oxford OX3 9DU, UK
| | - Lulia Al-Hillawi
- Translational Gastroenterology Unit, John Radcliffe Hospital, Oxford OX3 9DU, UK
| | - Sarah Sasson
- Translational Gastroenterology Unit, John Radcliffe Hospital, Oxford OX3 9DU, UK
| | - Stephanie Slevin
- Translational Gastroenterology Unit, John Radcliffe Hospital, Oxford OX3 9DU, UK
| | - Oliver Brain
- Translational Gastroenterology Unit, John Radcliffe Hospital, Oxford OX3 9DU, UK
| | - Ricardo A Fernandes
- Chinese Academy of Medical Sciences (CAMS) Oxford Institute (COI), University of Oxford, Oxford OX3 7BN, UK
| | - Hashem Koohy
- Medical Research Council (MRC) Translational Immune Discovery Unit, MRC Weatherall Institute of Molecular Medicine (WIMM), Radcliffe Department of Medicine, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DS, UK; MRC WIMM Centre For Computational Biology, MRC Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DS, UK.
| | - Alison Simmons
- Medical Research Council (MRC) Translational Immune Discovery Unit, MRC Weatherall Institute of Molecular Medicine (WIMM), Radcliffe Department of Medicine, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DS, UK; Translational Gastroenterology Unit, John Radcliffe Hospital, Oxford OX3 9DU, UK.
| |
Collapse
|
35
|
Kubat Oktem E. Biomarkers of Alzheimer's Disease Associated with Programmed Cell Death Reveal Four Repurposed Drugs. J Mol Neurosci 2024; 74:51. [PMID: 38700745 DOI: 10.1007/s12031-024-02228-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2023] [Accepted: 04/21/2024] [Indexed: 07/20/2024]
Abstract
Alzheimer's disease (AD) is a neurodegenerative disorder and the most common cause of dementia. Programmed cell death (PCD) is mainly characterized by unique morphological features and energy-dependent biochemical processes. The predominant pathway leading to cell death in AD has not been thoroughly analyzed, although there is evidence of neuron loss in AD and numerous pathways of PCD have been associated with this process. A better understanding of the systems biology underlying the relationship between AD and PCD could lead to the development of new therapeutic approaches. To this end, publicly available transcriptome data were examined using bioinformatic methods such as differential gene expression and weighted gene coexpression network analysis (WGCNA) to find PCD-related AD biomarkers. The diagnostic significance of these biomarkers was evaluated using a logistic regression-based predictive model. Using these biomarkers, a multifactorial regulatory network was developed. Last, a drug repositioning study was conducted to propose new drugs for the treatment of AD targeting PCD. The development of 3PM (predictive, preventive, and personalized) drugs for the treatment of AD would be enabled by additional research on the effects of these drugs on this disease.
Collapse
Affiliation(s)
- Elif Kubat Oktem
- Department of Molecular Biology and Genetics, Faculty of Engineering and Natural Sciences, Istanbul Medeniyet University, North Campus, Istanbul, 34700, Turkey.
| |
Collapse
|
36
|
Echeverría-Garcés G, Ramos-Medina MJ, Vargas R, Cabrera-Andrade A, Altamirano-Colina A, Freire MP, Montalvo-Guerrero J, Rivera-Orellana S, Echeverría-Espinoza P, Quiñones LA, López-Cortés A. Gastric cancer actionable genomic alterations across diverse populations worldwide and pharmacogenomics strategies based on precision oncology. Front Pharmacol 2024; 15:1373007. [PMID: 38756376 PMCID: PMC11096557 DOI: 10.3389/fphar.2024.1373007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2024] [Accepted: 04/10/2024] [Indexed: 05/18/2024] Open
Abstract
Introduction: Gastric cancer is one of the most prevalent types of cancer worldwide. The World Health Organization (WHO), the International Agency for Research on Cancer (IARC), and the Global Cancer Statistics (GLOBOCAN) reported an age standardized global incidence rate of 9.2 per 100,000 individuals for gastric cancer in 2022, with a mortality rate of 6.1. Despite considerable progress in precision oncology through the efforts of international consortia, understanding the genomic features and their influence on the effectiveness of anti-cancer treatments across diverse ethnic groups remains essential. Methods: Our study aimed to address this need by conducting integrated in silico analyses to identify actionable genomic alterations in gastric cancer driver genes, assess their impact using deleteriousness scores, and determine allele frequencies across nine global populations: European Finnish, European non-Finnish, Latino, East Asian, South Asian, African, Middle Eastern, Ashkenazi Jewish, and Amish. Furthermore, our goal was to prioritize targeted therapeutic strategies based on pharmacogenomics clinical guidelines, in silico drug prescriptions, and clinical trial data. Results: Our comprehensive analysis examined 275,634 variants within 60 gastric cancer driver genes from 730,947 exome sequences and 76,215 whole-genome sequences from unrelated individuals, identifying 13,542 annotated and predicted oncogenic variants. We prioritized the most prevalent and deleterious oncogenic variants for subsequent pharmacogenomics testing. Additionally, we discovered actionable genomic alterations in the ARID1A, ATM, BCOR, ERBB2, ERBB3, CDKN2A, KIT, PIK3CA, PTEN, NTRK3, TP53, and CDKN2A genes that could enhance the efficacy of anti-cancer therapies, as suggested by in silico drug prescription analyses, reviews of current pharmacogenomics clinical guidelines, and evaluations of phase III and IV clinical trials targeting gastric cancer driver proteins. Discussion: These findings underline the urgency of consolidating efforts to devise effective prevention measures, invest in genomic profiling for underrepresented populations, and ensure the inclusion of ethnic minorities in future clinical trials and cancer research in developed countries.
Collapse
Affiliation(s)
- Gabriela Echeverría-Garcés
- Centro de Referencia Nacional de Genómica, Secuenciación y Bioinformática, Instituto Nacional de Investigación en Salud Pública “Leopoldo Izquieta Pérez”, Quito, Ecuador
- Latin American Network for the Implementation and Validation of Clinical Pharmacogenomics Guidelines (RELIVAF-CYTED), Santiago, Chile
| | - María José Ramos-Medina
- German Cancer Research Center (DKFZ), Faculty of Biosciences, Heidelberg University, Heidelberg, Germany
| | - Rodrigo Vargas
- Latin American Network for the Implementation and Validation of Clinical Pharmacogenomics Guidelines (RELIVAF-CYTED), Santiago, Chile
- Department of Molecular Biology, Galileo University, Guatemala City, Guatemala
| | - Alejandro Cabrera-Andrade
- Escuela de Enfermería, Facultad de Ciencias de La Salud, Universidad de Las Américas, Quito, Ecuador
- Grupo de Bio-Quimioinformática, Universidad de Las Américas, Quito, Ecuador
| | | | - María Paula Freire
- Cancer Research Group (CRG), Faculty of Medicine, Universidad de Las Américas, Quito, Ecuador
| | | | | | | | - Luis A. Quiñones
- Latin American Network for the Implementation and Validation of Clinical Pharmacogenomics Guidelines (RELIVAF-CYTED), Santiago, Chile
- Laboratory of Chemical Carcinogenesis and Pharmacogenetics, Department of Basic-Clinical Oncology (DOBC), Faculty of Medicine, University of Chile, Santiago, Chile
- Department of Pharmaceutical Sciences and Technology, Faculty of Chemical and Pharmaceutical Sciences, University of Chile, Santiago, Chile
| | - Andrés López-Cortés
- Cancer Research Group (CRG), Faculty of Medicine, Universidad de Las Américas, Quito, Ecuador
| |
Collapse
|
37
|
Fitzpatrick AM, Huang M, Mohammad AF, Stephenson ST, Kamaleswaran R, Grunwell JR. Dysfunctional neutrophil type 1 interferon responses in preschool children with recurrent wheezing and IL-4-mediated aeroallergen sensitization. THE JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY. GLOBAL 2024; 3:100229. [PMID: 38510797 PMCID: PMC10950716 DOI: 10.1016/j.jacig.2024.100229] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/28/2023] [Revised: 11/25/2023] [Accepted: 12/24/2023] [Indexed: 03/22/2024]
Abstract
Background The innate mechanisms associated with viral exacerbations in preschool children with recurrent wheezing are not understood. Objective We sought to assess differential gene expression in blood neutrophils from preschool children with recurrent wheezing, stratified by aeroallergen sensitization, at baseline and after exposure to polyinosinic:polycytidylic acid (poly(I:C)) and also to examine whether poly(I:C)-stimulated blood neutrophils influenced airway epithelial gene expression. Methods Blood neutrophils were purified and cultured overnight with poly(I:C) and underwent next-generation sequencing with Reactome pathway analysis. Primary human small airway epithelial cells were treated with poly(I:C)-treated neutrophil culture supernatants and were analyzed for type 1 interferon gene expression with a targeted array. Symptoms and exacerbations were assessed in participants over 12 months. Results A total of 436 genes were differently expressed in neutrophils from children with versus without aeroallergen sensitization at baseline, with significant downregulation of type 1 interferons. These type 1 interferons were significantly upregulated in sensitized children after poly(I:C) stimulation. Confirmatory experiments demonstrated similar upregulation of type 1 interferons in IL-4-treated neutrophils stimulated with poly(I:C). Poly(I:C)-treated neutrophil supernatants from children with aeroallergen sensitization also induced a type 1 interferon response in epithelial cells. Children with aeroallergen sensitization also had higher symptom scores during exacerbations, and these symptom differences persisted for 3 days after prednisolone treatment. Conclusions Type 1 interferon responses are dysregulated in preschool children with aeroallergen sensitization, which is in turn associated with exacerbation severity. Given the importance of type 1 interferon signaling in viral resolution, additional studies of neutrophil type 1 interferon responses are needed in this population.
Collapse
Affiliation(s)
- Anne M. Fitzpatrick
- Department of Pediatrics, Emory University, Atlanta, Ga
- Division of Pulmonary Medicine, Children’s Healthcare of Atlanta, Atlanta, Ga
| | - Min Huang
- Department of Biomedical Informatics, Emory University, Atlanta, Ga
| | | | | | | | - Jocelyn R. Grunwell
- Department of Pediatrics, Emory University, Atlanta, Ga
- Division of Critical Care Medicine, Children’s Healthcare of Atlanta, Atlanta, Ga
| |
Collapse
|
38
|
DeBoer EM, Wolter-Warmerdam K, Deterding RR, Marmolejo J, Blumenthal T, Espinosa JM, Hickey F, Wagner BD. Cardiopulmonary Phenotypes and Protein Signatures in Children With Down Syndrome. Clin Pediatr (Phila) 2024; 63:474-481. [PMID: 37306037 PMCID: PMC11060669 DOI: 10.1177/00099228231179453] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 06/13/2023]
Abstract
Pulmonary disease, lower respiratory tract infection, and pneumonia are the largest causes of morbidity and mortality in individuals with Down syndrome (DS), but whether pulmonary diagnoses in children with DS are common and occur independently of cardiac disease and pulmonary hypertension (PH) is unknown. Cardiopulmonary phenotypes were examined in a cohort of 1248 children with DS. Aptamer-based proteomic analysis of blood was performed in a subset (n = 120) of these children. By the age of 10 years, half of the patients in this cohort (n = 634, 50.8%) had co-occurring pulmonary diagnoses. That proteins and related pathways were distinct between children with pulmonary diagnoses and those with cardiac disease and/or PH may indicate that pulmonary diagnoses appear to occur independently of cardiac disease and PH. Heparin sulfate-glycosaminoglycandegradation, nicotinate metabolism, and elastic fiber formation were ranked highest in the group with pulmonary diagnoses.
Collapse
Affiliation(s)
- Emily M. DeBoer
- Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO, USA
- Children’s Hospital Colorado, Aurora, CO, USA
- Linda Crnic Institute for Down Syndrome, University of Colorado School of Medicine, Aurora, CO, USA
| | | | - Robin R. Deterding
- Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO, USA
- Children’s Hospital Colorado, Aurora, CO, USA
| | | | - Tom Blumenthal
- Linda Crnic Institute for Down Syndrome, University of Colorado School of Medicine, Aurora, CO, USA
| | - Joaquin M. Espinosa
- Linda Crnic Institute for Down Syndrome, University of Colorado School of Medicine, Aurora, CO, USA
| | - Francis Hickey
- Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO, USA
- Children’s Hospital Colorado, Aurora, CO, USA
| | - Brandie D. Wagner
- Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO, USA
- Children’s Hospital Colorado, Aurora, CO, USA
- Department of Biostatistics & Informatics, University of Colorado School of Public Health, Aurora, CO, USA
| |
Collapse
|
39
|
Hemandhar Kumar S, Tapken I, Kuhn D, Claus P, Jung K. bootGSEA: a bootstrap and rank aggregation pipeline for multi-study and multi-omics enrichment analyses. FRONTIERS IN BIOINFORMATICS 2024; 4:1380928. [PMID: 38633435 PMCID: PMC11021641 DOI: 10.3389/fbinf.2024.1380928] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2024] [Accepted: 03/18/2024] [Indexed: 04/19/2024] Open
Abstract
Introduction: Gene set enrichment analysis (GSEA) subsequent to differential expression analysis is a standard step in transcriptomics and proteomics data analysis. Although many tools for this step are available, the results are often difficult to reproduce because set annotations can change in the databases, that is, new features can be added or existing features can be removed. Finally, such changes in set compositions can have an impact on biological interpretation. Methods: We present bootGSEA, a novel computational pipeline, to study the robustness of GSEA. By repeating GSEA based on bootstrap samples, the variability and robustness of results can be studied. In our pipeline, not all genes or proteins are involved in the different bootstrap replicates of the analyses. Finally, we aggregate the ranks from the bootstrap replicates to obtain a score per gene set that shows whether it gains or loses evidence compared to the ranking of the standard GSEA. Rank aggregation is also used to combine GSEA results from different omics levels or from multiple independent studies at the same omics level. Results: By applying our approach to six independent cancer transcriptomics datasets, we showed that bootstrap GSEA can aid in the selection of more robust enriched gene sets. Additionally, we applied our approach to paired transcriptomics and proteomics data obtained from a mouse model of spinal muscular atrophy (SMA), a neurodegenerative and neurodevelopmental disease associated with multi-system involvement. After obtaining a robust ranking at both omics levels, both ranking lists were combined to aggregate the findings from the transcriptomics and proteomics results. Furthermore, we constructed the new R-package "bootGSEA," which implements the proposed methods and provides graphical views of the findings. Bootstrap-based GSEA was able in the example datasets to identify gene or protein sets that were less robust when the set composition changed during bootstrap analysis. Discussion: The rank aggregation step was useful for combining bootstrap results and making them comparable to the original findings on the single-omics level or for combining findings from multiple different omics levels.
Collapse
Affiliation(s)
- Shamini Hemandhar Kumar
- Institute for Animal Genomics, University of Veterinary Medicine, Foundation, Hannover, Germany
- Center for Systems Neuroscience (ZSN), University of Veterinary Medicine, Foundation, Hannover, Germany
| | - Ines Tapken
- Center for Systems Neuroscience (ZSN), University of Veterinary Medicine, Foundation, Hannover, Germany
- SMATHERIA gGmbH—Non-Profit Biomedical Research Institute, Hannover, Germany
| | - Daniela Kuhn
- SMATHERIA gGmbH—Non-Profit Biomedical Research Institute, Hannover, Germany
- Clinic for Conservative Dentistry, Periodontology and Preventive Dentistry, Hannover Medical School, Hannover, Germany
| | - Peter Claus
- Center for Systems Neuroscience (ZSN), University of Veterinary Medicine, Foundation, Hannover, Germany
- SMATHERIA gGmbH—Non-Profit Biomedical Research Institute, Hannover, Germany
| | - Klaus Jung
- Institute for Animal Genomics, University of Veterinary Medicine, Foundation, Hannover, Germany
- Center for Systems Neuroscience (ZSN), University of Veterinary Medicine, Foundation, Hannover, Germany
| |
Collapse
|
40
|
Hu M, Alkhairy S, Lee I, Pillich RT, Fong D, Smith K, Bachelder R, Ideker T, Pratt D. Evaluation of large language models for discovery of gene set function. ARXIV 2024:arXiv:2309.04019v2. [PMID: 37731657 PMCID: PMC10508824] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Subscribe] [Scholar Register] [Indexed: 09/22/2023]
Abstract
Gene set analysis is a mainstay of functional genomics, but it relies on curated databases of gene functions that are incomplete. Here we evaluate five Large Language Models (LLMs) for their ability to discover the common biological functions represented by a gene set, substantiated by supporting rationale, citations and a confidence assessment. Benchmarking against canonical gene sets from the Gene Ontology, GPT-4 confidently recovered the curated name or a more general concept (73% of cases), while benchmarking against random gene sets correctly yielded zero confidence. Gemini-Pro and Mixtral-Instruct showed ability in naming but were falsely confident for random sets, whereas Llama2-70b had poor performance overall. In gene sets derived from 'omics data, GPT-4 identified novel functions not reported by classical functional enrichment (32% of cases), which independent review indicated were largely verifiable and not hallucinations. The ability to rapidly synthesize common gene functions positions LLMs as valuable 'omics assistants.
Collapse
Affiliation(s)
- Mengzhou Hu
- Department of Medicine, University of California San Diego, La Jolla, California, USA
| | - Sahar Alkhairy
- Department of Computer Science and Engineering, University of California San Diego, La Jolla, California, USA
| | - Ingoo Lee
- Department of Medicine, University of California San Diego, La Jolla, California, USA
| | - Rudolf T. Pillich
- Department of Medicine, University of California San Diego, La Jolla, California, USA
| | - Dylan Fong
- Department of Medicine, University of California San Diego, La Jolla, California, USA
| | - Kevin Smith
- Department of Physics, University of California San Diego, La Jolla, California, USA
| | - Robin Bachelder
- Department of Medicine, University of California San Diego, La Jolla, California, USA
| | - Trey Ideker
- Department of Medicine, University of California San Diego, La Jolla, California, USA
- Department of Computer Science and Engineering, University of California San Diego, La Jolla, California, USA
| | - Dexter Pratt
- Department of Medicine, University of California San Diego, La Jolla, California, USA
| |
Collapse
|
41
|
Kubat Öktem E, Yazar M, Aysan E, Karabıyık Acar Ö. Computational drug repurposing for primary hyperparathyroidism. Mol Cell Endocrinol 2024; 583:112159. [PMID: 38228226 DOI: 10.1016/j.mce.2024.112159] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/26/2023] [Revised: 11/17/2023] [Accepted: 01/12/2024] [Indexed: 01/18/2024]
Abstract
In hyperparathyroidism (hyperPTH), excessive amounts of PTH are secreted, interfering with calcium regulation in the body. Several drugs can control the disease's side effects, but none of them is an alternative treatment to surgery. Therefore, new drug candidates are necessary. In this study, three computationally repositioned drugs, DG 041, IMD 0354, and cucurbitacin I, are evaluated in an in vitro model of hyperPTH. First, we integrated publicly available transcriptomics datasets to propose drug candidates. Using 3D spheroids derived from a single primary hyperPTH patient, we assessed their in vitro efficacy. None of the proposed drugs affected the viability of healthy cell control (HEK293) or overactive parathyroid cells at the level of toxicity. This behavior was attributed to the non-cancerous nature of the parathyroid cells, establishing the hyperPTH disease model. Cucurbitacin I and IMD 0354 exhibited a slight inverse relationship between increased drug concentrations and cell viability, whereas DG 041 increased viability. Based on these results, further studies are needed on the mechanism of action of the repurposed drugs, including determining the effects of these drugs on cellular PTH synthesis and secretion and on the metabolic pathways that regulate PTH secretion.
Collapse
Affiliation(s)
- Elif Kubat Öktem
- Department of Molecular Biology and Genetics, Faculty of Engineering and Natural Sciences, Istanbul Medeniyet University, 34700, Istanbul, Turkey
| | - Metin Yazar
- Department of Genetics and Bioengineering, Faculty of Engineering and Natural Sciences, Istanbul Okan University, 34959, Istanbul, Turkey
| | - Erhan Aysan
- Department of General Surgery, Faculty of Medicine, Yeditepe University, 34718, Istanbul, Turkey
| | - Özge Karabıyık Acar
- Department of Genetics and Bioengineering, Faculty of Engineering and Natural Sciences, Istanbul Okan University, 34959, Istanbul, Turkey.
| |
Collapse
|
42
|
Jacobs JE, Davis L, McWeeney S. Single nucleotide variants in nuclear pore complex disassembly pathway associated with poor survival in osteosarcoma. Front Genet 2024; 15:1303404. [PMID: 38562379 PMCID: PMC10982431 DOI: 10.3389/fgene.2024.1303404] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2023] [Accepted: 03/01/2024] [Indexed: 04/04/2024] Open
Abstract
Introduction The bone tumor, osteosarcoma, remains challenging to treat in children and young adults, especially when patients present with metastatic disease. Developing new therapies based on genomic data from sequencing projects has proven difficult given the lack of recurrent genetic lesions across tumors. MYC overexpression has been associated with poor outcomes in osteosarcoma. However, other genomic markers of disease severity are lacking. Materials and Methods We utilized whole genome sequencing of 106 tumors and matched normal controls in order to define genomic characteristics that correlate with overall survival. Single nucleotide variants were overlaid onto annotated molecular pathways in order to define aberrant pathway signatures specific to aggressive osteosarcoma. Additionally, we calculated differential gene expression in a subsample of 71 tumors. Differentially expressed genes were then queried for known MYC-responsive genes. Results Molecular pathways specific to nuclear pore complex disassembly (NPCD) show significant correlation with poor overall survival in osteosarcoma when mutations were present. Genes involved in immune response and immune regulation are enriched in the differential expression analysis of samples with and without NPCD pathway aberrations. Furthermore, neither MYC nor MYC-responsive genes show differential expression between NPCD-aberrant and non-aberrant groups. The NPCD pathway mutations are dominated by regulatory region variants rather than protein-altering mutations, suggesting that dysregulation of genetic regulatory networks may be the underlying mechanism for their relation to osteosarcoma phenotype. Discussion Overall survival is significantly worse in patients whose tumors show aberrations in the NPCD pathway. Moreover, this difference in survival is not driven by MYC-overexpression, suggesting a novel mechanism for some aggressive osteosarcomas. These findings add light to the evolving understanding of the drivers of osteosarcoma and may aid in the search for new treatments based on patient-specific genetic data.
Collapse
Affiliation(s)
- James E. Jacobs
- Oregon Health & Science University, Portland, OR, United States
| | | | | |
Collapse
|
43
|
Bonora M, Morganti C, van Gastel N, Ito K, Calura E, Zanolla I, Ferroni L, Zhang Y, Jung Y, Sales G, Martini P, Nakamura T, Lasorsa FM, Finkel T, Lin CP, Zavan B, Pinton P, Georgakoudi I, Romualdi C, Scadden DT, Ito K. A mitochondrial NADPH-cholesterol axis regulates extracellular vesicle biogenesis to support hematopoietic stem cell fate. Cell Stem Cell 2024; 31:359-377.e10. [PMID: 38458178 PMCID: PMC10957094 DOI: 10.1016/j.stem.2024.02.004] [Citation(s) in RCA: 18] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2023] [Revised: 11/16/2023] [Accepted: 02/08/2024] [Indexed: 03/10/2024]
Abstract
Mitochondrial fatty acid oxidation (FAO) is essential for hematopoietic stem cell (HSC) self-renewal; however, the mechanism by which mitochondrial metabolism controls HSC fate remains unknown. Here, we show that within the hematopoietic lineage, HSCs have the largest mitochondrial NADPH pools, which are required for proper HSC cell fate and homeostasis. Bioinformatic analysis of the HSC transcriptome, biochemical assays, and genetic inactivation of FAO all indicate that FAO-generated NADPH fuels cholesterol synthesis in HSCs. Interference with FAO disturbs the segregation of mitochondrial NADPH toward corresponding daughter cells upon single HSC division. Importantly, we have found that the FAO-NADPH-cholesterol axis drives extracellular vesicle (EV) biogenesis and release in HSCs, while inhibition of EV signaling impairs HSC self-renewal. These data reveal the existence of a mitochondrial NADPH-cholesterol axis for EV biogenesis that is required for hematopoietic homeostasis and highlight the non-stochastic nature of HSC fate determination.
Collapse
Affiliation(s)
- Massimo Bonora
- Ruth L. and David S. Gottesman Institute for Stem Cell and Regenerative Medicine Research, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461, USA; Department of Cell Biology, Albert Einstein College of Medicine, Bronx, NY 10461, USA; Departments of Oncology and Medicine, Albert Einstein College of Medicine-Montefiore Health System, Bronx, NY 10461, USA
| | - Claudia Morganti
- Ruth L. and David S. Gottesman Institute for Stem Cell and Regenerative Medicine Research, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461, USA; Department of Cell Biology, Albert Einstein College of Medicine, Bronx, NY 10461, USA; Departments of Oncology and Medicine, Albert Einstein College of Medicine-Montefiore Health System, Bronx, NY 10461, USA
| | - Nick van Gastel
- Department of Stem Cell and Regenerative Biology, Harvard Stem Cell Institute, Harvard University, Cambridge, MA, USA; Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA, USA; de Duve Institute, UCLouvain, 1200 Brussels, Belgium
| | - Kyoko Ito
- Ruth L. and David S. Gottesman Institute for Stem Cell and Regenerative Medicine Research, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461, USA; Department of Cell Biology, Albert Einstein College of Medicine, Bronx, NY 10461, USA; Departments of Oncology and Medicine, Albert Einstein College of Medicine-Montefiore Health System, Bronx, NY 10461, USA
| | - Enrica Calura
- Department of Biology, University of Padova, 35121 Padua, Italy
| | - Ilaria Zanolla
- Department of Medical Sciences, University of Ferrara, 44121 Ferrara, Italy
| | - Letizia Ferroni
- Maria Cecilia Hospital, GVM Care & Research, Cotignola, 48033 Ravenna, Italy
| | - Yang Zhang
- Department of Biomedical Engineering, Tufts University, 4 Colby St, Medford, MA 02155, USA
| | - Yookyung Jung
- Department of Biomedical Engineering, Tufts University, 4 Colby St, Medford, MA 02155, USA; Department of Pathology, Albert Einstein College of Medicine, Bronx, NY 10461, USA; Gruss-Lipper Biophotonics Center, Albert Einstein College of Medicine, Bronx, NY 10461, USA
| | - Gabriele Sales
- Department of Biology, University of Padova, 35121 Padua, Italy
| | - Paolo Martini
- Department of Molecular and Translational Medicine, University of Brescia, 25121 Brescia, Italy
| | - Takahisa Nakamura
- Divisions of Endocrinology and Developmental Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45229, USA; Department of Metabolic Bioregulation, Institute of Development, Aging and Cancer, Tohoku University, Sendai 980-8575, Japan
| | - Francesco Massimo Lasorsa
- Department of Biosciences Biotechnologies and Environment University of Bari and Institute of Biomembranes Bioenergetics and Molecular Biotechnologies, Consiglio Nazionale delle Ricerche, 70125 Bari, Italy
| | - Toren Finkel
- Aging Institute and Department of Medicine, University of Pittsburgh School of Medicine/University of Pittsburgh Medical Center, Pittsburgh, PA 15261, USA
| | - Charles P Lin
- Center for Systems Biology and Wellman Center for Photomedicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA
| | - Barbara Zavan
- Maria Cecilia Hospital, GVM Care & Research, Cotignola, 48033 Ravenna, Italy; Laboratory for Technologies of Advanced Therapies (LTTA), University of Ferrara, 44121 Ferrara, Italy; Translational Medicine Department, University of Ferrara, 44121 Ferrara, Italy
| | - Paolo Pinton
- Department of Medical Sciences, University of Ferrara, 44121 Ferrara, Italy; Maria Cecilia Hospital, GVM Care & Research, Cotignola, 48033 Ravenna, Italy; Laboratory for Technologies of Advanced Therapies (LTTA), University of Ferrara, 44121 Ferrara, Italy
| | - Irene Georgakoudi
- Department of Biomedical Engineering, Tufts University, 4 Colby St, Medford, MA 02155, USA
| | - Chiara Romualdi
- Department of Biology, University of Padova, 35121 Padua, Italy
| | - David T Scadden
- Department of Stem Cell and Regenerative Biology, Harvard Stem Cell Institute, Harvard University, Cambridge, MA, USA; Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA, USA
| | - Keisuke Ito
- Ruth L. and David S. Gottesman Institute for Stem Cell and Regenerative Medicine Research, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461, USA; Department of Cell Biology, Albert Einstein College of Medicine, Bronx, NY 10461, USA; Departments of Oncology and Medicine, Albert Einstein College of Medicine-Montefiore Health System, Bronx, NY 10461, USA; Montefiore Einstein Comprehensive Cancer Center and Diabetes Research Center, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
| |
Collapse
|
44
|
de Almeida V, Mendes ND, Zuccoli GS, Reis-de-Oliveira G, Almeida GM, Podolsky-Gondim GG, Neder L, Martins-de-Souza D, Sebollela A. NMDA glutamate receptor antagonist MK-801 induces proteome changes in adult human brain slices which are partially counteracted by haloperidol and clozapine. J Neurochem 2024; 168:238-250. [PMID: 38332572 DOI: 10.1111/jnc.16059] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2023] [Revised: 11/27/2023] [Accepted: 01/04/2024] [Indexed: 02/10/2024]
Abstract
Deciphering the molecular pathways associated with N-methyl-D-aspartate receptor (NMDAr) hypofunction and its interaction with antipsychotics is necessary to advance our understanding of the basis of schizophrenia, as well as our capacity to treat this disease. In this regard, the development of human brain-derived models that are amenable to studying the neurobiology of schizophrenia may contribute to filling the gaps left by the widely employed animal models. Here, we assessed the proteomic changes induced by the NMDA glutamate receptor antagonist MK-801 on human brain slice cultures obtained from adult donors submitted to respective neurosurgery. Initially, we demonstrated that MK-801 diminishes NMDA glutamate receptor signaling in human brain slices in culture. Next, using mass-spectrometry-based proteomics and systems biology in silico analyses, we found that MK-801 led to alterations in proteins related to several pathways previously associated with schizophrenia pathophysiology, including ephrin, opioid, melatonin, sirtuin signaling, interleukin 8, endocannabinoid, and synaptic vesicle cycle. We also evaluated the impact of both typical and atypical antipsychotics on MK-801-induced proteome changes. Interestingly, the atypical antipsychotic clozapine showed a more significant capacity to counteract the protein alterations induced by NMDAr hypofunction than haloperidol. Finally, using our dataset, we identified potential modulators of the MK-801-induced proteome changes, which may be considered promising targets to treat NMDAr hypofunction in schizophrenia. This dataset is publicly available and may be helpful in further studies aimed at evaluating the effects of MK-801 and antipsychotics in the human brain.
Collapse
Affiliation(s)
- Valéria de Almeida
- Laboratory of Neuroproteomics, Department of Biochemistry and Tissue Biology, Institute of Biology, University of Campinas (UNICAMP), Campinas, Brazil
| | - Niele Dias Mendes
- Department of Biochemistry and Immunology, Ribeirao Preto Medical School, University of Sao Paulo, Sao Paulo, Brazil
- Department of Pathology and Forensic Medicine, Ribeirao Preto Medical School, University of Sao Paulo, Sao Paulo, Brazil
- Division of Neurosurgery, Department of Surgery and Anatomy, Ribeirão Preto Medical School, University of São Paulo, Sao Paulo, Brazil
| | - Giuliana S Zuccoli
- Laboratory of Neuroproteomics, Department of Biochemistry and Tissue Biology, Institute of Biology, University of Campinas (UNICAMP), Campinas, Brazil
| | - Guilherme Reis-de-Oliveira
- Laboratory of Neuroproteomics, Department of Biochemistry and Tissue Biology, Institute of Biology, University of Campinas (UNICAMP), Campinas, Brazil
| | - Glaucia M Almeida
- Department of Biochemistry and Immunology, Ribeirao Preto Medical School, University of Sao Paulo, Sao Paulo, Brazil
| | - Guilherme Gozzoli Podolsky-Gondim
- Division of Neurosurgery, Department of Surgery and Anatomy, Ribeirão Preto Medical School, University of São Paulo, Sao Paulo, Brazil
| | - Luciano Neder
- Department of Pathology and Forensic Medicine, Ribeirao Preto Medical School, University of Sao Paulo, Sao Paulo, Brazil
| | - Daniel Martins-de-Souza
- Laboratory of Neuroproteomics, Department of Biochemistry and Tissue Biology, Institute of Biology, University of Campinas (UNICAMP), Campinas, Brazil
- Instituto Nacional de Biomarcadores em Neuropsiquiatria (INBION) Conselho Nacional de Desenvolvimento Científico e Tecnológico, Sao Paulo, Brazil
- Experimental Medicine Research Cluster (EMRC), University of Campinas, Campinas, Sao Paulo, Brazil
- D'Or Institute for Research and Education (IDOR), Sao Paulo, Brazil
| | - Adriano Sebollela
- Department of Biochemistry and Immunology, Ribeirao Preto Medical School, University of Sao Paulo, Sao Paulo, Brazil
| |
Collapse
|
45
|
Langan LM, Lovin LM, Taylor RB, Scarlett KR, Kevin Chambliss C, Chatterjee S, Scott JT, Brooks BW. Proteome changes in larval zebrafish (Danio rerio) and fathead minnow (Pimephales promelas) exposed to (±) anatoxin-a. ENVIRONMENT INTERNATIONAL 2024; 185:108514. [PMID: 38394915 DOI: 10.1016/j.envint.2024.108514] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/15/2023] [Revised: 02/16/2024] [Accepted: 02/17/2024] [Indexed: 02/25/2024]
Abstract
Anatoxin-a and its analogues are potent neurotoxins produced by several genera of cyanobacteria. Due in part to its high toxicity and potential presence in drinking water, these toxins pose threats to public health, companion animals and the environment. It primarily exerts toxicity as a cholinergic agonist, with high affinity at neuromuscular junctions, but molecular mechanisms by which it elicits toxicological responses are not fully understood. To advance understanding of this cyanobacteria, proteomic characterization (DIA shotgun proteomics) of two common fish models (zebrafish and fathead minnow) was performed following (±) anatoxin-a exposure. Specifically, proteome changes were identified and quantified in larval fish exposed for 96 h (0.01-3 mg/L (±) anatoxin-a and caffeine (a methodological positive control) with environmentally relevant treatment levels examined based on environmental exposure distributions of surface water data. Proteomic concentration - response relationships revealed 48 and 29 proteins with concentration - response relationships curves for zebrafish and fathead minnow, respectively. In contrast, the highest number of differentially expressed proteins (DEPs) varied between zebrafish (n = 145) and fathead minnow (n = 300), with only fatheads displaying DEPs at all treatment levels. For both species, genes associated with reproduction were significantly downregulated, with pathways analysis that broadly clustered genes into groups associated with DNA repair mechanisms. Importantly, significant differences in proteome response between the species was also observed, consistent with prior observations of differences in response using both behavioral assays and gene expression, adding further support to model specific differences in organismal sensitivity and/or response. When DEPs were read across from humans to zebrafish, disease ontology enrichment identified diseases associated with cognition and muscle weakness consistent with the prior literature. Our observations highlight limited knowledge of how (±) anatoxin-a, a commonly used synthetic racemate surrogate, elicits responses at a molecular level and advances its toxicological understanding.
Collapse
Affiliation(s)
- Laura M Langan
- Department of Environmental Science, Baylor University, Waco, TX 76798, USA; Center for Reservoir and Aquatic Systems Research, Baylor University, Waco, TX 76798, USA; Department of Environmental Health Sciences, University of South Carolina, Columbia, SC 29208, USA.
| | - Lea M Lovin
- Department of Environmental Science, Baylor University, Waco, TX 76798, USA; Center for Reservoir and Aquatic Systems Research, Baylor University, Waco, TX 76798, USA; Department of Wildlife, Fish and Environmental Studies, Swedish University of Agricultural Sciences, Umeå, Sweden
| | - Raegyn B Taylor
- Center for Reservoir and Aquatic Systems Research, Baylor University, Waco, TX 76798, USA; Department of Chemistry, Baylor University, Waco, TX 76798, USA
| | - Kendall R Scarlett
- Department of Environmental Science, Baylor University, Waco, TX 76798, USA; Center for Reservoir and Aquatic Systems Research, Baylor University, Waco, TX 76798, USA
| | - C Kevin Chambliss
- Center for Reservoir and Aquatic Systems Research, Baylor University, Waco, TX 76798, USA; Department of Chemistry, Baylor University, Waco, TX 76798, USA
| | - Saurabh Chatterjee
- Department of Medicine, Department of Environmental and Occupational Health, University of California Irvine, Irvine, CA 92617, USA
| | - J Thad Scott
- Center for Reservoir and Aquatic Systems Research, Baylor University, Waco, TX 76798, USA; Department of Biology, Baylor University, Waco, TX 76798, USA
| | - Bryan W Brooks
- Department of Environmental Science, Baylor University, Waco, TX 76798, USA; Center for Reservoir and Aquatic Systems Research, Baylor University, Waco, TX 76798, USA.
| |
Collapse
|
46
|
Shrestha S, Taujale R, Katiyar S, Kannan N. Illuminating the functions of the understudied Fructosamine-3-kinase (FN3K) using a multi-omics approach reveals new links to lipid, carbon, and co-factor metabolic pathways. RESEARCH SQUARE 2024:rs.3.rs-3934957. [PMID: 38410452 PMCID: PMC10896376 DOI: 10.21203/rs.3.rs-3934957/v1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/28/2024]
Abstract
Fructosamine-3-kinases (FN3Ks) are a conserved family of repair enzymes that phosphorylate reactive sugars attached to lysine residues in peptides and proteins. Although FN3Ks are present across the tree of life and share detectable sequence similarity to eukaryotic protein kinases, the biological processes regulated by these kinases are largely unknown. To address this knowledge gap, we leveraged the FN3K CRISPR Knock-Out (KO) cell line alongside an integrative multi-omics study combining transcriptomics, metabolomics, and interactomics to place these enzymes in a pathway context. The integrative analyses revealed the enrichment of pathways related to oxidative stress response, lipid biosynthesis (cholesterol and fatty acids), carbon and co-factor metabolism. Moreover, enrichment of nicotinamide adenine dinucleotide (NAD) binding proteins and localization of human FN3K (HsFN3K) to mitochondria suggests potential links between FN3Ks and NAD-mediated energy metabolism and redox balance. We report specific binding of HsFN3K to NAD compounds in a metal and concentration-dependent manner and provide insight into their binding mode using modeling and experimental site-directed mutagenesis. By identifying a potential link between FN3Ks, redox regulation, and NAD-dependent metabolic processes, our studies provide a framework for targeting these understudied kinases in diabetic complications and metabolic disorders where redox balance is altered.
Collapse
Affiliation(s)
- Safal Shrestha
- Institute of Bioinformatics; University of Georgia, Athens, GA, USA
| | - Rahil Taujale
- Department of Biochemistry and Molecular Biology; University of Georgia, Athens, GA, USA
| | - Samiksha Katiyar
- Department of Biochemistry and Molecular Biology; University of Georgia, Athens, GA, USA
| | - Natarajan Kannan
- Institute of Bioinformatics; University of Georgia, Athens, GA, USA
- Department of Biochemistry and Molecular Biology; University of Georgia, Athens, GA, USA
| |
Collapse
|
47
|
Luo H, Huemer MT, Petrera A, Hauck SM, Rathmann W, Herder C, Koenig W, Hoyer A, Peters A, Thorand B. Association of plasma proteomics with incident coronary heart disease in individuals with and without type 2 diabetes: results from the population-based KORA study. Cardiovasc Diabetol 2024; 23:53. [PMID: 38310303 PMCID: PMC10838466 DOI: 10.1186/s12933-024-02143-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/13/2023] [Accepted: 01/22/2024] [Indexed: 02/05/2024] Open
Abstract
BACKGROUND Coronary heart disease (CHD) is a major global health concern, especially among individuals with type 2 diabetes (T2D). Given the crucial role of proteins in various biological processes, this study aimed to elucidate the aetiological role and predictive performance of protein biomarkers on incident CHD in individuals with and without T2D. METHODS The discovery cohort included 1492 participants from the Cooperative Health Research in the Region of Augsburg (KORA) S4 study with 147 incident CHD cases (45 vs. 102 cases in the group with T2D and without T2D, respectively) during 15.6 years of follow-up. The validation cohort included 888 participants from the KORA-Age1 study with 70 incident CHD cases (19 vs. 51 cases in the group with T2D and without T2D, respectively) during 6.9 years of follow-up. We measured 233 plasma proteins related to cardiovascular disease and inflammation using proximity extension assay technology. Associations of proteins with incident CHD were assessed using Cox regression and Mendelian randomization (MR) analysis. Predictive models were developed using priority-Lasso and were evaluated on top of Framingham risk score variables using the C-index, category-free net reclassification index (cfNRI), and relative integrated discrimination improvement (IDI). RESULTS We identified two proteins associated with incident CHD in individuals with and 29 in those without baseline T2D, respectively. Six of these proteins are novel candidates for incident CHD. MR suggested a potential causal role for hepatocyte growth factor in CHD development. The developed four-protein-enriched model for individuals with baseline T2D (ΔC-index: 0.017; cfNRI: 0.253; IDI: 0.051) and the 12-protein-enriched model for individuals without baseline T2D (ΔC-index: 0.054; cfNRI: 0.462; IDI: 0.024) consistently improved CHD prediction in the discovery cohort, while in the validation cohort, significant improvements were only observed for selected performance measures (with T2D: cfNRI: 0.633; without T2D: ΔC-index: 0.038; cfNRI: 0.465). CONCLUSIONS This study identified novel protein biomarkers associated with incident CHD in individuals with and without T2D and reaffirmed previously reported protein candidates. These findings enhance our understanding of CHD pathophysiology and provide potential targets for prevention and treatment.
Collapse
Affiliation(s)
- Hong Luo
- Institute of Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), Ingolstaedter Landstraße 1, D-85764, Neuherberg, Germany
- Institute for Medical Information Processing, Biometry and Epidemiology (IBE), Faculty of Medicine, LMU Munich, Pettenkofer School of Public Health, Munich, Germany
| | - Marie-Theres Huemer
- Institute of Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), Ingolstaedter Landstraße 1, D-85764, Neuherberg, Germany
| | - Agnese Petrera
- Metabolomics and Proteomics Core, Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), Neuherberg, Germany
| | - Stefanie M Hauck
- Metabolomics and Proteomics Core, Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), Neuherberg, Germany
- German Center for Diabetes Research (DZD), Partner München-Neuherberg, Neuherberg, Germany
| | - Wolfgang Rathmann
- Institute for Biometrics and Epidemiology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine Universität, Düsseldorf, Germany
- German Center for Diabetes Research (DZD), Partner Düsseldorf, Neuherberg, Germany
| | - Christian Herder
- German Center for Diabetes Research (DZD), Partner Düsseldorf, Neuherberg, Germany
- Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine Universität, Düsseldorf, Germany
- Department of Endocrinology and Diabetology, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine Universität, Düsseldorf, Germany
| | - Wolfgang Koenig
- Institute of Epidemiology and Medical Biometry, University of Ulm, Ulm, Germany
- Deutsches Herzzentrum München, Technische Universität München, Munich, Germany
- German Centre for Cardiovascular Research (DZHK), Partner Site Munich Heart Alliance, Munich, Germany
| | - Annika Hoyer
- Biostatistics and Medical Biometry, Medical School OWL, Bielefeld University, Bielefeld, Germany
| | - Annette Peters
- Institute of Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), Ingolstaedter Landstraße 1, D-85764, Neuherberg, Germany
- Institute for Medical Information Processing, Biometry and Epidemiology (IBE), Faculty of Medicine, LMU Munich, Pettenkofer School of Public Health, Munich, Germany
- German Center for Diabetes Research (DZD), Partner München-Neuherberg, Neuherberg, Germany
- German Centre for Cardiovascular Research (DZHK), Partner Site Munich Heart Alliance, Munich, Germany
| | - Barbara Thorand
- Institute of Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), Ingolstaedter Landstraße 1, D-85764, Neuherberg, Germany.
- Institute for Medical Information Processing, Biometry and Epidemiology (IBE), Faculty of Medicine, LMU Munich, Pettenkofer School of Public Health, Munich, Germany.
- German Center for Diabetes Research (DZD), Partner München-Neuherberg, Neuherberg, Germany.
| |
Collapse
|
48
|
Ramos-Medina MJ, Echeverría-Garcés G, Kyriakidis NC, León Cáceres Á, Ortiz-Prado E, Bautista J, Pérez-Meza ÁA, Abad-Sojos A, Nieto-Jaramillo K, Espinoza-Ferrao S, Ocaña-Paredes B, López-Cortés A. CardiOmics signatures reveal therapeutically actionable targets and drugs for cardiovascular diseases. Heliyon 2024; 10:e23682. [PMID: 38187312 PMCID: PMC10770621 DOI: 10.1016/j.heliyon.2023.e23682] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2023] [Revised: 11/27/2023] [Accepted: 12/09/2023] [Indexed: 01/09/2024] Open
Abstract
Cardiovascular diseases are the leading cause of death worldwide, with heart failure being a complex condition that affects millions of individuals. Single-nucleus RNA sequencing has recently emerged as a powerful tool for unraveling the molecular mechanisms behind cardiovascular diseases. This cutting-edge technology enables the identification of molecular signatures, intracellular networks, and spatial relationships among cardiac cells, including cardiomyocytes, mast cells, lymphocytes, macrophages, lymphatic endothelial cells, endocardial cells, endothelial cells, epicardial cells, adipocytes, fibroblasts, neuronal cells, pericytes, and vascular smooth muscle cells. Despite these advancements, the discovery of essential therapeutic targets and drugs for precision cardiology remains a challenge. To bridge this gap, we conducted comprehensive in silico analyses of single-nucleus RNA sequencing data, functional enrichment, protein interactome network, and identification of the shortest pathways to physiological phenotypes. This integrated multi-omics analysis generated CardiOmics signatures, which allowed us to pinpoint three therapeutically actionable targets (ADRA1A1, PPARG, and ROCK2) and 15 effective drugs, including adrenergic receptor agonists, adrenergic receptor antagonists, norepinephrine precursors, PPAR receptor agonists, and Rho-associated kinase inhibitors, involved in late-stage cardiovascular disease clinical trials.
Collapse
Affiliation(s)
- María José Ramos-Medina
- German Cancer Research Center (DKFZ), Faculty of Biosciences, Heidelberg University, Heidelberg, Germany
| | - Gabriela Echeverría-Garcés
- Centro de Referencia Nacional de Genómica, Secuenciación y Bioinformática, Instituto Nacional de Investigación en Salud Pública “Leopoldo Izquieta Pérez”, Quito, Ecuador
- Latin American Network for the Implementation and Validation of Clinical Pharmacogenomics Guidelines (RELIVAF-CYTED), Santiago, Chile
| | - Nikolaos C. Kyriakidis
- Cancer Research Group (CRG), Faculty of Medicine, Universidad de Las Américas, Quito, Ecuador
| | - Ángela León Cáceres
- Heidelberg Institute of Global Health, Faculty of Medicine, University of Heidelberg, Heidelberg, Germany
- Instituto de Salud Pública, Facultad de Medicina, Pontificia Universidad Católica del Ecuador, Quito, Ecuador
| | - Esteban Ortiz-Prado
- One Health Research Group, Faculty of Medicine, Universidad de Las Américas, Quito, Ecuador
| | - Jhommara Bautista
- Cancer Research Group (CRG), Faculty of Medicine, Universidad de Las Américas, Quito, Ecuador
| | - Álvaro A. Pérez-Meza
- Escuela de Medicina, Colegio de Ciencias de La Salud COCSA, Universidad San Francisco de Quito USFQ, Quito, Ecuador
| | | | - Karol Nieto-Jaramillo
- School of Biological Sciences and Engineering, Yachay Tech University, Urcuqui, Ecuador
| | | | - Belén Ocaña-Paredes
- Cancer Research Group (CRG), Faculty of Medicine, Universidad de Las Américas, Quito, Ecuador
| | - Andrés López-Cortés
- Cancer Research Group (CRG), Faculty of Medicine, Universidad de Las Américas, Quito, Ecuador
| |
Collapse
|
49
|
Guito JC, Arnold CE, Schuh AJ, Amman BR, Sealy TK, Spengler JR, Harmon JR, Coleman-McCray JD, Sanchez-Lockhart M, Palacios GF, Towner JS, Prescott JB. Peripheral immune responses to filoviruses in a reservoir versus spillover hosts reveal transcriptional correlates of disease. Front Immunol 2024; 14:1306501. [PMID: 38259437 PMCID: PMC10800976 DOI: 10.3389/fimmu.2023.1306501] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2023] [Accepted: 11/27/2023] [Indexed: 01/24/2024] Open
Abstract
Several filoviruses, including Marburg virus (MARV), cause severe disease in humans and nonhuman primates (NHPs). However, the Egyptian rousette bat (ERB, Rousettus aegyptiacus), the only known MARV reservoir, shows no overt illness upon natural or experimental infection, which, like other bat hosts of zoonoses, is due to well-adapted, likely species-specific immune features. Despite advances in understanding reservoir immune responses to filoviruses, ERB peripheral blood responses to MARV and how they compare to those of diseased filovirus-infected spillover hosts remain ill-defined. We thus conducted a longitudinal analysis of ERB blood gene responses during acute MARV infection. These data were then contrasted with a compilation of published primate blood response studies to elucidate gene correlates of filovirus protection versus disease. Our work expands on previous findings in MARV-infected ERBs by supporting both host resistance and disease tolerance mechanisms, offers insight into the peripheral immunocellular repertoire during infection, and provides the most direct known cross-examination between reservoir and spillover hosts of the most prevalently-regulated response genes, pathways and activities associated with differences in filovirus pathogenesis and pathogenicity.
Collapse
Affiliation(s)
- Jonathan C. Guito
- Viral Special Pathogens Branch, Division of High-Consequence Pathogens and Pathology, Centers for Disease Control and Prevention, Atlanta, GA, United States
| | - Catherine E. Arnold
- Biological Defense Research Directorate, Naval Medical Research Center, Frederick, MD, United States
- RD-CBR, Research and Development Directorate, Chemical and Biological Technologies Directorate, Research Center of Excellence, Defense Threat Reduction Agency, Fort Belvoir, VA, United States
| | - Amy J. Schuh
- Viral Special Pathogens Branch, Division of High-Consequence Pathogens and Pathology, Centers for Disease Control and Prevention, Atlanta, GA, United States
| | - Brian R. Amman
- Viral Special Pathogens Branch, Division of High-Consequence Pathogens and Pathology, Centers for Disease Control and Prevention, Atlanta, GA, United States
| | - Tara K. Sealy
- Viral Special Pathogens Branch, Division of High-Consequence Pathogens and Pathology, Centers for Disease Control and Prevention, Atlanta, GA, United States
| | - Jessica R. Spengler
- Viral Special Pathogens Branch, Division of High-Consequence Pathogens and Pathology, Centers for Disease Control and Prevention, Atlanta, GA, United States
| | - Jessica R. Harmon
- Viral Special Pathogens Branch, Division of High-Consequence Pathogens and Pathology, Centers for Disease Control and Prevention, Atlanta, GA, United States
| | - Joann D. Coleman-McCray
- Viral Special Pathogens Branch, Division of High-Consequence Pathogens and Pathology, Centers for Disease Control and Prevention, Atlanta, GA, United States
| | - Mariano Sanchez-Lockhart
- Center for Genome Sciences, Molecular Biology Division, U.S. Army Medical Research Institute of Infectious Diseases, Fort Detrick, MD, United States
| | - Gustavo F. Palacios
- Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, United States
| | - Jonathan S. Towner
- Viral Special Pathogens Branch, Division of High-Consequence Pathogens and Pathology, Centers for Disease Control and Prevention, Atlanta, GA, United States
| | - Joseph B. Prescott
- Viral Special Pathogens Branch, Division of High-Consequence Pathogens and Pathology, Centers for Disease Control and Prevention, Atlanta, GA, United States
- Center for Biological Threats and Special Pathogens, Robert Koch Institute, Berlin, Germany
| |
Collapse
|
50
|
Wishart DS, Kruger R, Sivakumaran A, Harford K, Sanford S, Doshi R, Khetarpal N, Fatokun O, Doucet D, Zubkowski A, Jackson H, Sykes G, Ramirez-Gaona M, Marcu A, Li C, Yee K, Garros C, Rayat D, Coleongco J, Nandyala T, Gautam V, Oler E. PathBank 2.0-the pathway database for model organism metabolomics. Nucleic Acids Res 2024; 52:D654-D662. [PMID: 37962386 PMCID: PMC10767802 DOI: 10.1093/nar/gkad1041] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2023] [Revised: 10/19/2023] [Accepted: 10/31/2023] [Indexed: 11/15/2023] Open
Abstract
PathBank (https://pathbank.org) and its predecessor database, the Small Molecule Pathway Database (SMPDB), have been providing comprehensive metabolite pathway information for the metabolomics community since 2010. Over the past 14 years, these pathway databases have grown and evolved significantly to meet the needs of the metabolomics community and respond to continuing changes in computing technology. This year's update, PathBank 2.0, brings a number of important improvements and upgrades that should make the database more useful and more appealing to a larger cross-section of users. In particular, these improvements include: (i) a significant increase in the number of primary or canonical pathways (from 1720 to 6951); (ii) a massive increase in the total number of pathways (from 110 234 to 605 359); (iii) significant improvements to the quality of pathway diagrams and pathway descriptions; (iv) a strong emphasis on drug metabolism and drug mechanism pathways; (v) making most pathway images more slide-compatible and manuscript-compatible; (vi) adding tools to support better pathway filtering and selecting through a more complete pathway taxonomy; (vii) adding pathway analysis tools for visualizing and calculating pathway enrichment. Many other minor improvements and updates to the content, the interface and general performance of the PathBank website have also been made. Overall, we believe these upgrades and updates should greatly enhance PathBank's ease of use and its potential applications for interpreting metabolomics data.
Collapse
Affiliation(s)
- David S Wishart
- Department of Biological Sciences, University of Alberta, Edmonton, AB T6G 2E9, Canada
- Department of Computing Science, University of Alberta, Edmonton, AB T6G 2E8, Canada
- Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, AB T6G 2B7, Canada
- Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, AB T6G 2H7, Canada
| | - Ray Kruger
- Department of Biological Sciences, University of Alberta, Edmonton, AB T6G 2E9, Canada
| | - Aadhavya Sivakumaran
- Department of Biological Sciences, University of Alberta, Edmonton, AB T6G 2E9, Canada
| | - Karxena Harford
- Department of Biological Sciences, University of Alberta, Edmonton, AB T6G 2E9, Canada
| | - Selena Sanford
- Department of Biological Sciences, University of Alberta, Edmonton, AB T6G 2E9, Canada
| | - Rahil Doshi
- Department of Biological Sciences, University of Alberta, Edmonton, AB T6G 2E9, Canada
| | - Nitya Khetarpal
- Department of Biological Sciences, University of Alberta, Edmonton, AB T6G 2E9, Canada
| | - Omolola Fatokun
- Department of Biological Sciences, University of Alberta, Edmonton, AB T6G 2E9, Canada
| | - Daphnee Doucet
- Department of Biological Sciences, University of Alberta, Edmonton, AB T6G 2E9, Canada
| | - Ashley Zubkowski
- Department of Biological Sciences, University of Alberta, Edmonton, AB T6G 2E9, Canada
| | - Hayley Jackson
- Department of Biological Sciences, University of Alberta, Edmonton, AB T6G 2E9, Canada
| | - Gina Sykes
- Department of Biological Sciences, University of Alberta, Edmonton, AB T6G 2E9, Canada
| | - Miguel Ramirez-Gaona
- Department of Plant Breeding, Wageningen University and Research, 6708 PBWageningen, Gelderland, Netherlands
| | - Ana Marcu
- Department of Biological Sciences, University of Alberta, Edmonton, AB T6G 2E9, Canada
| | - Carin Li
- Department of Biological Sciences, University of Alberta, Edmonton, AB T6G 2E9, Canada
| | - Kristen Yee
- Department of Biological Sciences, University of Alberta, Edmonton, AB T6G 2E9, Canada
| | - Christiana Garros
- Department of Biological Sciences, University of Alberta, Edmonton, AB T6G 2E9, Canada
| | - Dorsa Yahya Rayat
- Department of Biological Sciences, University of Alberta, Edmonton, AB T6G 2E9, Canada
| | - Jeanne Coleongco
- Department of Biological Sciences, University of Alberta, Edmonton, AB T6G 2E9, Canada
| | - Tharuni Nandyala
- Department of Biological Sciences, University of Alberta, Edmonton, AB T6G 2E9, Canada
| | - Vasuk Gautam
- Department of Biological Sciences, University of Alberta, Edmonton, AB T6G 2E9, Canada
| | - Eponine Oler
- Department of Biological Sciences, University of Alberta, Edmonton, AB T6G 2E9, Canada
| |
Collapse
|