EBioMedicine最新文献

{"title":"Predicting Clostridioides difficile infection outcomes with explainable machine learning.","authors":"Gregory R Madden, Rachel H Boone, Emmanuel Lee, Costi D Sifri, William A Petri","doi":"10.1016/j.ebiom.2024.105244","DOIUrl":"10.1016/j.ebiom.2024.105244","url":null,"abstract":"<p><strong>Background: </strong>Clostridioides difficile infection results in life-threatening short-term outcomes and the potential for subsequent recurrent infection. Predicting these outcomes at diagnosis, when important clinical decisions need to be made, has proven to be a difficult task.</p><p><strong>Methods: </strong>52 clinical features from existing models or the literature were collected retrospectively within ±48 h of diagnosis among 1660 inpatient infections. A modified desirability of outcome ranking (DOOR) was designed to encompass clinically-important severe events attributable to the acute infection (intensive care transfer due to sepsis, shock, colectomy/ileostomy, mortality) and/or 60-day recurrence. A deep neural network was constructed and interpreted using SHapley Additive exPlanations (SHAP). High-importance features were used to train a reduced, shallow network and performance was compared to existing conventional models (7 severity, 7 recurrence; after summing DOOR probabilities to align with conventional binary outputs) using area under the ROC curve (AUROC) and DeLong tests.</p><p><strong>Findings: </strong>The full (52-feature) model achieved an out-of-sample AUROC 0.823 for severity and 0.678 for recurrence. SHAP identified 13 unique, highly-important features (age, hypotension, initial treatment, onset, PCR cycle threshold, number of prior episodes, antibiotic exposure, fever, hypotension, pressors, leukocytosis, creatinine, lactate) that were used to train a reduced model, which performed similarly to the full model (severity AUROC difference P = 0.130; recurrence P = 0.426) and significantly better than the top severity model (reduced model predicting severity 0.837, ATLAS 0.749; P = 0.001). The reduced model also outperformed the top recurrence model, but this was not statistically-significant (reduced model recurrence AUROC 0.653, IDSA Recurrence Risk Criteria 0.595; P = 0.196). The final, reduced model was deployed as a web application with real-time SHAP explanations.</p><p><strong>Interpretation: </strong>Our final model outperformed existing severity and recurrence models; however, it requires external validation. A DOOR output allows specific clinical questions to be asked with explainable predictions that can be feasibly implemented with limited computing resources.</p><p><strong>Funding: </strong>National Institutes of Health-Institute of Allergy and Infectious Diseases.</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":null,"pages":null},"PeriodicalIF":9.7,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11286990/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141633032","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Distinguishing recrudescence from reinfection in lymphatic filariasis.","authors":"Young-Jun Choi, Kerstin Fischer, Aboulaye Méité, Benjamin G Koudou, Peter U Fischer, Makedonka Mitreva","doi":"10.1016/j.ebiom.2024.105188","DOIUrl":"10.1016/j.ebiom.2024.105188","url":null,"abstract":"<p><strong>Background: </strong>The Global Program to Eliminate Lymphatic Filariasis (GPELF) is the largest public health program based on mass drug administration (MDA). Despite decades of MDA, ongoing transmission in some countries remains a challenge. To optimise interventions, it is critical to differentiate between recrudescence and new infections. Since adult filariae are inaccessible in humans, deriving a method that relies on the offspring microfilariae (mf) is necessary.</p><p><strong>Methods: </strong>We developed a genome amplification and kinship analysis-based approach using Brugia malayi samples from gerbils, and applied it to analyse Wuchereria bancrofti mf from humans in Côte d'Ivoire. We examined the pre-treatment genetic diversity in 269 mf collected from 18 participants, and further analysed 1-year post-treatment samples of 74 mf from 4 participants. Hemizygosity of the male X-chromosome allowed for direct inference of haplotypes, facilitating robust maternal parentage inference. To enrich parasite DNA from samples contaminated with host DNA, a whole-exome capture panel was created for W. bancrofti.</p><p><strong>Findings: </strong>By reconstructing and temporally tracking sibling relationships across pre- and post-treatment samples, we differentiated between new and established maternal families, suggesting reinfection in one participant and recrudescence in three participants. The estimated number of reproductively active adult females ranged between 3 and 11 in the studied participants. Population structure analysis revealed genetically distinct parasites in Côte d'Ivoire compared to samples from other countries. Exome capture identified protein-coding variants with ∼95% genotype concordance rate.</p><p><strong>Interpretation: </strong>We have generated resources to facilitate the development of molecular genetic tools that can estimate adult worm burdens and monitor parasite populations, thus providing essential information for the successful implementation of GPELF.</p><p><strong>Funding: </strong>This work was financially supported by the Bill and Melinda Gates Foundation (https://www.gatesfoundation.org) under grant OPP1201530 (Co-PIs PUF & Gary J. Weil). B. malayi parasite material was generated with support of the Foundation for Barnes Jewish Hospital (PUF). In addition, the development of computational methods was supported by the National Institutes of Health under grants AI144161 (MM) and AI146353 (MM). The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":null,"pages":null},"PeriodicalIF":9.7,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11200287/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141287886","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Seroprevalence of human immunodeficiency virus in African blood donors: a systematic review and meta-analysis.","authors":"Angelina Edna Quintas, Nelson Cuboia, Lemuel Cordeiro, António Sarmento, Luís Azevedo","doi":"10.1016/j.ebiom.2024.105210","DOIUrl":"10.1016/j.ebiom.2024.105210","url":null,"abstract":"<p><strong>Background: </strong>In developing countries, the safety of blood transfusions remains an important public health concern as it is associated with a higher risk of transfusion-transmissible infections (TTIs). In this study, we aimed to estimate the seroprevalence of HIV among blood donors in Africa and assess the temporal trends and regional differences within the continent through a systematic review and meta-analysis.</p><p><strong>Methods: </strong>Seven electronic databases (PubMed, Web of Science, Cochrane, Scopus, HINARI, Global Index Medicus and Clinical.</p><p><strong>Trial: </strong>gov) were searched for relevant studies for our research. We included all primary studies that estimated the seroprevalence of HIV among blood donors in Africa with an age population from 16 to 65 years old, without language restrictions, from inception up to March 1st 2024. The pooled seroprevalence was estimated through the DerSimonian-Laird random effects model. The temporal trends and regional differences were assessed through subgroup and meta-regression analysis.</p><p><strong>Findings: </strong>We obtained 122 studies that met our inclusion criteria, comprising 7,814,996 blood donors tested for HIV. Sixty-six percent of the studies were from Western and Eastern Africa. The pooled seroprevalence of HIV among blood donors in Africa was 2.66% (95% CI: 2.17-3.20%; I² = 99.80%, p < 0.01). The highest prevalence was observed in the Central African region, 3.28% (95% CI: 2.57%-4.06%), followed by the Eastern 3.21% (95% CI: 2.12%-4.52%), and the Western 2.66% (95% CI: 1.93%-3.49%) regions. Lower prevalences were observed in the Northern region, 0.57% (95% CI: 0.0%-2.10%), followed by the Southern African region with 0.45% (95% CI: 0.16%-0.86%). We observed a temporal decreased trend of HIV prevalence.</p><p><strong>Interpretation: </strong>The prevalence of HIV infection among African blood donors remains high and is not homogeneous across the continent. Efficient measures to strengthen HIV testing and prevent HIV transmission through blood transfusion are needed in Africa. Systematic review protocol registration: PROSPERO CRD42023395616.</p><p><strong>Funding: </strong>This article was supported by National Funds through FCT - Fundação para a Ciência e a Tecnologia,I.P., within CINTESIS, R&D Unit (reference UIDP/4255/2020).</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":null,"pages":null},"PeriodicalIF":9.7,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11260585/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141466945","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Longitudinal changes in iron homeostasis in human experimental and clinical malaria.","authors":"Stephen D Woolley, Matthew J Grigg, Louise Marquart, Jeremy S E Gower, Kim Piera, Arya Sheela Nair, Fiona M Amante, Giri S Rajahram, Timothy William, David M Frazer, Stephan Chalon, James S McCarthy, Nicholas M Anstey, Bridget E Barber","doi":"10.1016/j.ebiom.2024.105189","DOIUrl":"10.1016/j.ebiom.2024.105189","url":null,"abstract":"<p><strong>Background: </strong>The interaction between iron status and malaria is incompletely understood. We evaluated longitudinal changes in iron homeostasis in volunteers enrolled in malaria volunteer infection studies (VIS) and in Malaysian patients with falciparum and vivax malaria.</p><p><strong>Methods: </strong>We retrieved data and samples from 55 participants (19 female) enrolled in malaria VIS, and 171 patients (45 female) with malaria and 30 healthy controls (13 female) enrolled in clinical studies in Malaysia. Ferritin, hepcidin, erythropoietin, and soluble transferrin receptor (sTfR) were measured by ELISA.</p><p><strong>Findings: </strong>In the VIS, participants' parasitaemia was correlated with baseline mean corpuscular volume (MCV), but not iron status (ferritin, hepcidin or sTfR). Ferritin, hepcidin and sTfR all increased during the VIS. Ferritin and hepcidin normalised by day 28, while sTfR remained elevated. In VIS participants, baseline ferritin was associated with post-treatment increases in liver transaminase levels. In Malaysian patients with malaria, hepcidin and ferritin were elevated on admission compared to healthy controls, while sTfR increased following admission. By day 28, hepcidin had normalised; however, ferritin and sTfR both remained elevated.</p><p><strong>Interpretation: </strong>Our findings demonstrate that parasitaemia is associated with an individual's MCV rather than iron status. The persistent elevation in sTfR 4 weeks post-infection in both malaria VIS and clinical malaria may reflect a causal link between malaria and iron deficiency.</p><p><strong>Funding: </strong>National Health and Medical Research Council (Program Grant 1037304, Project Grants 1045156 and 1156809; Investigator Grants 2016792 to BEB, 2016396 to JCM, 2017436 to MJG); US National Institute of Health (R01-AI116472-03); Malaysian Ministry of Health (BP00500420).</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":null,"pages":null},"PeriodicalIF":9.7,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11200279/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141293286","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Post-COVID-19 condition, brain fog, and fatigue-what do we know now?","authors":"eBioMedicine","doi":"10.1016/j.ebiom.2024.105252","DOIUrl":"10.1016/j.ebiom.2024.105252","url":null,"abstract":"","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":null,"pages":null},"PeriodicalIF":9.7,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11293575/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141598921","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A computational framework to improve cross-platform implementation of transcriptomics signatures.","authors":"Louis Kreitmann, Giselle D'Souza, Luca Miglietta, Ortensia Vito, Heather R Jackson, Dominic Habgood-Coote, Michael Levin, Alison Holmes, Myrsini Kaforou, Jesus Rodriguez-Manzano","doi":"10.1016/j.ebiom.2024.105204","DOIUrl":"10.1016/j.ebiom.2024.105204","url":null,"abstract":"<p><p>The emergence of next-generation sequencing technologies and computational advances have expanded our understanding of gene expression regulation (i.e., the transcriptome). This has also led to an increased interest in using transcriptomic biomarkers to improve disease diagnosis and stratification, to assess prognosis and predict the response to treatment. Significant progress in identifying transcriptomic signatures for various clinical needs has been made, with large discovery studies accounting for challenges such as patient variability, unwanted batch effects, and data complexities; however, obstacles related to the technical aspects of cross-platform implementation still hinder the successful integration of transcriptomic technologies into standard diagnostic workflows. In this article, we discuss the challenges associated with integrating transcriptomic signatures derived using high-throughput technologies (such as RNA-sequencing) into clinical diagnostic tools using nucleic acid amplification (NAA) techniques. The novelty of the proposed approach lies in our aim to embed constraints related to cross-platform implementation in the process of signature discovery. These constraints could include technical limitations of amplification platform and chemistry, the maximal number of targets imposed by the chosen multiplexing strategy, and the genomic context of identified RNA biomarkers. Finally, we propose to build a computational framework that would integrate these constraints in combination with existing statistical and machine learning models used for signature identification. We envision that this could accelerate the integration of RNA signatures discovered by high-throughput technologies into NAA-based approaches suitable for clinical applications.</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":null,"pages":null},"PeriodicalIF":9.7,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11245942/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141431599","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Durability of immunity and clinical protection in nursing home residents following bivalent SARS-CoV-2 vaccination.","authors":"Stefan Gravenstein, Frank DeVone, Oladayo A Oyebanji, Yasin Abul, Yi Cao, Philip A Chan, Christopher W Halladay, James L Rudolph, Clare Nugent, Jürgen Bosch, Christopher L King, Brigid M Wilson, Alejandro B Balazs, Elizabeth M White, David H Canaday, Kevin W McConeghy","doi":"10.1016/j.ebiom.2024.105180","DOIUrl":"10.1016/j.ebiom.2024.105180","url":null,"abstract":"<p><strong>Background: </strong>Bivalent SARS-CoV-2 vaccines were developed to counter increasing susceptibility to emerging SARS-CoV-2 variants. We evaluated the durability of immunity and protection following first bivalent vaccination among nursing home residents.</p><p><strong>Methods: </strong>We evaluated anti-spike and neutralization titers from blood in 653 community nursing home residents before and after each monovalent booster, and a bivalent vaccine. Concurrent clinical outcomes were evaluated using electronic health record data from a separate cohort of 3783 residents of Veterans Affairs (VA) nursing homes who had received at least the primary series monovalent vaccination. Using target trial emulation, we compared VA residents who did and did not receive the bivalent vaccine to measure vaccine effectiveness against infection, hospitalization, and death.</p><p><strong>Findings: </strong>In the community cohort, Omicron BA.5 neutralization activity rose after each monovalent and bivalent booster vaccination regardless of prior infection history. Titers declined over time but six months post-bivalent vaccination, BA.5 neutralization persisted at detectable levels in 75% of infection-naive and 98% of prior-infected individuals. In the VA nursing home cohort, bivalent vaccine added effectiveness to monovalent booster vaccination by 18.5% for infection (95% confidence interval (CI) -5.6, 34.0%), and 29.2% for hospitalization or death (95% CI -14.2, 56.2%) over five months.</p><p><strong>Interpretation: </strong>The level of protection declined after bivalent vaccination over a 6 month period and may open a window of added vulnerability before the next updated vaccine becomes available, suggesting a subset of nursing home residents may benefit from an additional vaccination booster.</p><p><strong>Funding: </strong>CDC, NIH, VHA.</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":null,"pages":null},"PeriodicalIF":9.7,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11215210/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141305696","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Exploratory multi-omics analysis reveals host-microbe interactions associated with disease severity in psoriatic skin.","authors":"Ying Yang, Peter Olah, Zoltan Radai, Guilherme Maia, Alexander Salava, Ville Salo, Jonathan Barker, Antti Lauerma, Björn Andersson, Bernhard Homey, Nanna Fyhrquist, Harri Alenius","doi":"10.1016/j.ebiom.2024.105222","DOIUrl":"10.1016/j.ebiom.2024.105222","url":null,"abstract":"<p><strong>Background: </strong>Psoriasis (Pso) is a chronic inflammatory skin disease that poses both physical and psychological challenges. Dysbiosis of the skin microbiome has been implicated in Pso, yet a comprehensive multi-omics analysis of host-microbe interactions is still lacking. To bridge this gap, we conducted an exploratory study by adopting the integrated approach that combines whole metagenomic shotgun sequencing with skin transcriptomics.</p><p><strong>Methods: </strong>This was a cross-sectional study, adult patients with plaque-type Psoriasis (Pso) and healthy volunteers were included. Skin microbiota samples and biopsies were collected from both lesional and non-lesional skin areas on the lower back. Weighted Gene Correlation Network Analysis (WGCNA) was employed for co-expression network analysis, and cell deconvolution was conducted to estimate cell fractions. Taxonomic and functional features of the microbiome were identified using whole metagenomic shotgun sequencing. Association between host genes and microbes was analyzed using Spearman correlation.</p><p><strong>Findings: </strong>Host anti-viral responses and interferon-related networks were identified and correlated with the severity of psoriasis. The skin microbiome showed a greater prevalence of Corynebacterium simulans in the PASI severe-moderate groups, which correlated with interferon-induced host genes. Two distinct psoriatic clusters with varying disease severities were identified. Variations in the expression of cell apoptosis-associated antimicrobial peptides (AMPs) and microbial aerobic respiration I pathway may partly account for these differences in disease severity.</p><p><strong>Interpretation: </strong>Our multi-omics analysis revealed for the first time anti-viral responses and the presence of C. simulans associated with psoriasis severity. It also identified two psoriatic subtypes with distinct AMP and metabolic pathway expression. Our study provides new insights into understanding the host-microbe interaction in psoriasis and lays the groundwork for developing subtype-specific strategies for managing this chronic skin disease.</p><p><strong>Funding: </strong>The research has received funding from the FP7 (MAARS-Grant 261366) and the Innovative Medicines Initiative 2 Joint Undertaking (JU) under grant agreement No 821511 (BIOMAP). The JU receives support from the European Union's Horizon 2020 research and innovation programme and EFPIA. This publication reflects only the author's view and the JU is not responsible for any use that may be made of the information it contains. GAM was supported by a scholarship provided by CAPES-PRINT, financed by the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - CAPES (Brazilian Government Agency). The authors thank all patients who participated in our study.</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":null,"pages":null},"PeriodicalIF":9.7,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11259698/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141455955","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Advancing drug development for atrial fibrillation by prioritising findings from human genetic association studies.","authors":"Kishore Kukendrarajah, Aliki-Eleni Farmaki, Pier D Lambiase, Richard Schilling, Chris Finan, Amand Floriaan Schmidt, Rui Providencia","doi":"10.1016/j.ebiom.2024.105194","DOIUrl":"10.1016/j.ebiom.2024.105194","url":null,"abstract":"<p><strong>Background: </strong>Drug development for atrial fibrillation (AF) has failed to yield new approved compounds. We sought to identify and prioritise potential druggable targets with support from human genetics, by integrating the available evidence with bioinformatics sources relevant for AF drug development.</p><p><strong>Methods: </strong>Genetic hits for AF and related traits were identified through structured search of MEDLINE. Genes derived from each paper were cross-referenced with the OpenTargets platform for drug interactions. Confirmation/validation was demonstrated through structured searches and review of evidence on MEDLINE and ClinialTrials.gov for each drug and its association with AF.</p><p><strong>Findings: </strong>613 unique drugs were identified, with 21 already included in AF Guidelines. Cardiovascular drugs from classes not currently used for AF (e.g. ranolazine and carperitide) and anti-inflammatory drugs (e.g. dexamethasone and mehylprednisolone) had evidence of potential benefit. Further targets were considered druggable but remain open for drug development.</p><p><strong>Interpretation: </strong>Our systematic approach, combining evidence from different bioinformatics platforms, identified drug repurposing opportunities and druggable targets for AF.</p><p><strong>Funding: </strong>KK is supported by Barts Charity grant G-002089 and is mentored on the AFGen 2023-24 Fellowship funded by the AFGen NIH/NHLBI grant R01HL092577. RP is supported by the UCL BHF Research Accelerator AA/18/6/34223 and NIHR grant NIHR129463. AFS is supported by the BHF grants PG/18/5033837, PG/22/10989 and UCL BHF Accelerator AA/18/6/34223 as well as the UK Research and Innovation (UKRI) under the UK government's Horizon Europe funding guarantee EP/Z000211/1 and by the UKRI-NIHR grant MR/V033867/1 for the Multimorbidity Mechanism and Therapeutics Research Collaboration. AF is supported by UCL BHF Accelerator AA/18/6/34223. CF is supported by UCL BHF Accelerator AA/18/6/34223.</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":null,"pages":null},"PeriodicalIF":9.7,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11260865/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141466940","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Enhancer demethylation-regulated gene score identified molecular subtypes, inspiring immunotherapy or CDK4/6 inhibitor therapy in oesophageal squamous cell carcinoma.","authors":"Wenyan Gao, Shi Liu, Yenan Wu, Wenqing Wei, Qi Yang, Wenxin Li, Hongyan Chen, Aiping Luo, Yanfeng Wang, Zhihua Liu","doi":"10.1016/j.ebiom.2024.105177","DOIUrl":"10.1016/j.ebiom.2024.105177","url":null,"abstract":"<p><strong>Background: </strong>The 5-year survival rate of oesophageal squamous cell carcinoma (ESCC) is approximately 20%. The prognosis and drug response exhibit substantial heterogeneity in ESCC, impeding progress in survival outcomes. Our goal is to identify a signature for tumour subtype classification, enabling precise clinical treatments.</p><p><strong>Methods: </strong>Utilising pre-treatment multi-omics data from an ESCC dataset (n = 310), an enhancer methylation-eRNA-target gene regulation network was constructed and validated by in vitro experiments. Four machine learning methods collectively identified core target genes, establishing an Enhancer Demethylation-Regulated Gene Score (EDRGS) model for classification. The molecular function of EDRGS subtyping was explored in scRNA-seq (n = 60) and bulk-seq (n = 310), and the EDRGS's potential to predict treatment response was assessed in datasets of various cancer types.</p><p><strong>Findings: </strong>EDRGS stratified ESCCs into EDRGS-high/low subtypes, with EDRGS-high signifying a less favourable prognosis in ESCC and nine additional cancer types. EDRGS-high exhibited an immune-hot but immune-suppressive phenotype with elevated immune checkpoint expression, increased T cell infiltration, and IFNγ signalling in ESCC, suggesting a better response to immunotherapy. Notably, EDRGS outperformed PD-L1 in predicting anti-PD-1/L1 therapy effectiveness in ESCC (n = 42), kidney renal clear cell carcinoma (KIRC, n = 181), and bladder urothelial carcinoma (BLCA, n = 348) cohorts. EDRGS-low showed a cell cycle-activated phenotype with higher CDK4 and/or CDK6 expression, demonstrating a superior response to the CDK4/6 inhibitor palbociclib, validated in ESCC (n = 26), melanoma (n = 18), prostate cancer (n = 15) cells, and PDX models derived from patients with pancreatic cancer (n = 30).</p><p><strong>Interpretation: </strong>Identification of EDRGS subtypes enlightens ESCC categorisation, offering clinical insights for patient management in immunotherapy (anti-PD-1/L1) and CDK4/6 inhibitor therapy across cancer types.</p><p><strong>Funding: </strong>This study was supported by funding from the National Key R&D Program of China (2021YFC2501000, 2020YFA0803300), the National Natural Science Foundation of China (82030089, 82188102), the CAMS Innovation Fund for Medical Sciences (2021-I2M-1-018, 2022-I2M-2-001, 2021-I2M-1-067), the Fundamental Research Funds for the Central Universities (3332021091).</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":null,"pages":null},"PeriodicalIF":9.7,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11259699/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141455954","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}