EBioMedicine最新文献

{"title":"Simplifying coronary artery disease risk stratification: development and validation of a questionnaire-based alternative comparable to clinical risk tools.","authors":"Michail Kokkorakis, Pytrik Folkertsma, Filippos Anagnostakis, Nicole Sirotin, Manyoo Agarwal, Ronney Shantouf, Robert H Henning, Hanno Pijl, Bruce H R Wolffenbuttel, Jeroen J Bax, Douwe E Atsma, José Castela Forte, Christos S Mantzoros, Sipko van Dam","doi":"10.1016/j.ebiom.2024.105518","DOIUrl":"10.1016/j.ebiom.2024.105518","url":null,"abstract":"<p><strong>Background: </strong>Coronary artery disease (CAD) comprises one of the leading causes of morbidity and mortality both in the European population and globally. All established clinical risk stratification scores and models require blood lipids and physical measurements. The latest reports of the European Commission suggest that attracting health professionals to collect these data can be challenging, both from a logistic and cost perspective, which limits the usefulness of established models and makes them unsuitable for population-wide screening in resource-limited settings, i.e., rural areas. Therefore, the aim of this study was to develop and externally validate a questionnaire-based risk stratification model on a population scale at minimal cost, i.e., the Questionnaire-Based Evaluation for Estimating Coronary Artery Disease (QUES-CAD) to stratify the 10-year incidence of coronary artery disease.</p><p><strong>Methods: </strong>Cox proportional hazards (CoxPH) and Cox gradient boosting (CoxGBT) models were trained with 10-fold cross-validation using combinations of ten questionnaire variables on the White population of the UK Biobank (n = 448,818) and internally validated the models in all ethnic minorities (n = 27,433). The Lifelines cohort was employed as an independent external validation population (n = 97,770). Additionally, we compared QUES-CAD's performance, containing only questionnaire variables, to clinically established risk prediction tools, i.e., Framingham Coronary Heart Disease Risk Score, American College of Cardiology/American Heart Association pooled cohort equation, World Health Organization cardiovascular disease risk charts, and Systematic Coronary Risk Estimation 2 (SCORE2). We conducted partial log-likelihood ratio (PLR) tests and C-index comparisons between QUES-CAD and established clinical prediction models.</p><p><strong>Findings: </strong>In the external validation set, QUES-CAD exhibited C-index values of CoxPH: 0.692 (95% Confidence Interval [CI]: 0.673-0.71) and CoxGBT: 0.699 (95% CI: 0.681-0.717) for the male population and CoxPH: 0.771 (95% CI: 0.748-0.794) and CoxGBT: 0.759 (95% CI: 0.736-0.783) for the female population. The addition of measurement-based variables and variables that require a prior medical examination (i.e., insulin use, number of treatments/medications taken, prevalent cardiovascular disease [other than CAD, and stroke diagnosed by a doctor]) and the further addition of biomarkers/other measurements (i.e., high-density lipoprotein [HDL] cholesterol, total cholesterol, and glycated haemoglobin) did not significantly improve QUES-CAD's performance in most instances. C-index comparisons and PLR tests showed that QUES-CAD performs and fits the data at least as well as the clinical prediction models.</p><p><strong>Interpretation: </strong>QUES-CAD performs comparably to established clinical prediction models and enables a population-wide identification of high-risk individuals for CAD.","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":"111 ","pages":"105518"},"PeriodicalIF":9.7,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11732493/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142892914","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":"Hypothalamic volume is associated with age, sex and cognitive function across lifespan: a comparative analysis of two large population-based cohort studies.","authors":"Peng Xu, Santiago Estrada, Rika Etteldorf, Dan Liu, Mohammad Shahid, Weiyi Zeng, Deborah Früh, Martin Reuter, Monique M B Breteler, N Ahmad Aziz","doi":"10.1016/j.ebiom.2024.105513","DOIUrl":"10.1016/j.ebiom.2024.105513","url":null,"abstract":"<p><strong>Background: </strong>Emerging findings indicate that the hypothalamus, the body's principal homeostatic centre, plays a crucial role in modulating cognition, but comprehensive population-based studies are lacking.</p><p><strong>Methods: </strong>We used cross-sectional data from the Rhineland Study (N = 5812, 55.2 ± 13.6 years, 58% women) and the UK Biobank Imaging Study (UKB) (N = 45,076, 64.2 ± 7.7 years, 53% women), two large-scale population-based cohort studies. Volumes of hypothalamic structures were obtained from 3T structural magnetic resonance images through an automatic parcellation procedure (FastSurfer-HypVINN). The standardised cognitive domain scores were derived from extensive neuropsychological test batteries. We employed multivariable linear regression to assess associations of hypothalamic volumes with age, sex and cognitive performance.</p><p><strong>Findings: </strong>In older individuals, volumes of total, anterior and posterior hypothalamus, and mammillary bodies were smaller, while those of medial hypothalamus and tuberal region were larger. Larger medial hypothalamus volume was related to higher cortisol levels in older individuals, providing functional validation. Volumes of all hypothalamic structures were larger in men compared to women. In both sexes, larger volumes of total, anterior and posterior hypothalamus, and mammillary bodies were associated with better domain-specific cognitive performance, whereas larger volumes of medial hypothalamus and tuberal region were associated with worse domain-specific cognitive performance.</p><p><strong>Interpretation: </strong>We found strong age and sex effects on hypothalamic structures, as well as robust associations between these structures and domain-specific cognitive functions. Overall, these findings thus implicate specific hypothalamic subregions as potential therapeutic targets against age-associated cognitive decline.</p><p><strong>Funding: </strong>Institutional funds, Federal Ministry of Education and Research of Germany, Alzheimer's Association.</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":"111 ","pages":"105513"},"PeriodicalIF":9.7,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11732039/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142871704","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":"3D ultrasound localization microscopy of the nonhuman primate brain.","authors":"Paul Xing, Vincent Perrot, Adan Ulises Dominguez-Vargas, Jonathan Porée, Stephan Quessy, Numa Dancause, Jean Provost","doi":"10.1016/j.ebiom.2024.105457","DOIUrl":"10.1016/j.ebiom.2024.105457","url":null,"abstract":"<p><strong>Background: </strong>Haemodynamic changes occur in stroke and neurodegenerative diseases. Developing imaging techniques allowing the in vivo visualisation and quantification of cerebral blood flow would help better understand the underlying mechanism of these cerebrovascular diseases.</p><p><strong>Methods: </strong>3D ultrasound localization microscopy (ULM) is a recently developed technology that can map the microvasculature of the brain at large depth and has been mainly used until now in rodents. In this study, we tested the feasibility of 3D ULM of the nonhuman primate (NHP) brain with a single 256-channel programmable ultrasound scanner.</p><p><strong>Findings: </strong>We achieved a highly resolved vascular map of the macaque brain at large depth (down to 3 cm) in presence of craniotomy and durectomy using an 8-MHz multiplexed matrix probe. We were able to distinguish vessels as small as 26.9 μm. We also demonstrated that transcranial imaging of the macaque brain at similar depth was feasible using a 3-MHz probe and achieved a resolution of 60 μm.</p><p><strong>Interpretation: </strong>This work paves the way to clinical applications of 3D ULM. In particular, transcranial 3D ULM in humans could become a tool for the non-invasive study and monitoring of the brain cerebrovascular changes occurring in neurological diseases.</p><p><strong>Funding: </strong>This work was supported by the New Frontier in Research Fund (NFRFE-2022-00590), by the Canada Foundation for Innovation under grant 38095, by the Natural Sciences and Engineering Research Council of Canada (NSERC) under discovery grant RGPIN-2020-06786, by Brain Canada under grant PSG2019, and by the Canadian Institutes of Health Research (CIHR) under grant PJT-156047 and MPI-452530. Computing support was provided by the Digital Research Alliance of Canada.</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":"111 ","pages":"105457"},"PeriodicalIF":9.7,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11730257/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142871702","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":"Shared genetic architecture and bidirectional clinical risks within the psycho-metabolic nexus.","authors":"Xiaonan Guo, Yu Feng, Xiaolong Ji, Ningning Jia, Aierpati Maimaiti, Jianbo Lai, Zheng Wang, Sheng Yang, Shaohua Hu","doi":"10.1016/j.ebiom.2024.105530","DOIUrl":"10.1016/j.ebiom.2024.105530","url":null,"abstract":"<p><strong>Background: </strong>Increasing evidence suggests a complex interplay between psychiatric disorders and metabolic dysregulations. However, most research has been limited to specific disorder pairs, leaving a significant gap in our understanding of the broader psycho-metabolic nexus.</p><p><strong>Methods: </strong>This study leveraged large-scale cohort data and genome-wide association study (GWAS) summary statistics, covering 8 common psychiatric disorders and 43 metabolic traits. We introduced a comprehensive analytical strategy to identify shared genetic bases sequentially, from key genetic correlation regions to local pleiotropy and pleiotropic genes. Finally, we developed polygenic risk score (PRS) models to translate these findings into clinical applications.</p><p><strong>Findings: </strong>We identified significant bidirectional clinical risks between psychiatric disorders and metabolic dysregulations among 310,848 participants from the UK Biobank. Genetic correlation analysis confirmed 104 robust trait pairs, revealing 1088 key genomic regions, including critical hotspots such as chr3: 47588462-50387742. Cross-trait meta-analysis uncovered 388 pleiotropic single nucleotide variants (SNVs) and 126 shared causal variants. Among variants, 45 novel SNVs were associated with psychiatric disorders and 75 novel SNVs were associated with metabolic traits, shedding light on new targets to unravel the mechanism of comorbidity. Notably, RBM6, a gene involved in alternative splicing and cellular stress response regulation, emerged as a key pleiotropic gene. When psychiatric and metabolic genetic information were integrated, PRS models demonstrated enhanced predictive power.</p><p><strong>Interpretation: </strong>The study highlights the intertwined genetic and clinical relationships between psychiatric disorders and metabolic dysregulations, emphasising the need for integrated approaches in diagnosis and treatment.</p><p><strong>Funding: </strong>The National Key Research and Development Program of China (2023YFC2506200, SHH). The National Natural Science Foundation of China (82273741, SY).</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":"111 ","pages":"105530"},"PeriodicalIF":9.7,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11743124/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142892523","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":"Why implementing machine learning algorithms in the clinic is not a plug-and-play solution: a simulation study of a machine learning algorithm for acute leukaemia subtype diagnosis.","authors":"Gernot Pucher, Till Rostalski, Felix Nensa, Jens Kleesiek, Hans Christian Reinhardt, Christopher Martin Sauer","doi":"10.1016/j.ebiom.2024.105526","DOIUrl":"10.1016/j.ebiom.2024.105526","url":null,"abstract":"<p><strong>Background: </strong>Artificial intelligence (AI) and machine learning (ML) algorithms have shown great promise in clinical medicine. Despite the increasing number of published algorithms, most remain unvalidated in real-world clinical settings. This study aims to simulate the practical implementation challenges of a recently developed ML algorithm, AI-PAL, designed for the diagnosis of acute leukaemia and report on its performance.</p><p><strong>Methods: </strong>We conducted a detailed simulation of the AI-PAL algorithm's implementation at the University Hospital Essen. Cohort building was performed using our Fast Healthcare Interoperability Resources (FHIR) database, identifying all initially diagnosed patients with acute leukaemia and selected differential diagnoses. The algorithm's performance was assessed by reproducing the original study's results.</p><p><strong>Findings: </strong>The AI-PAL algorithm demonstrated significantly lower performance in our simulated clinical implementation compared to prior published results. The area under the receiver operating characteristic curve for acute lymphoblastic leukaemia dropped to 0.67 (95% CI: 0.61-0.73) and for acute myeloid leukaemia to 0.71 (95% CI: 0.65-0.76). The recalibration of probability cutoffs determining confident diagnoses increased the number of confident positive diagnosis for acute leukaemia from 98 to 160, highlighting the necessity of local validation and adjustments.</p><p><strong>Interpretation: </strong>The findings underscore the challenges of implementing ML algorithms in clinical practice. Despite robust development and validation in research settings, ML models like AI-PAL may require significant adjustments and recalibration to maintain performance in different clinical settings. Our results suggest that clinical decision support algorithms should undergo local performance validation before integration into routine care to ensure reliability and safety.</p><p><strong>Funding: </strong>This study was supported by the DFG-cofounded UMEA Clinician Scientist Program and the Ministry of Culture and Science of the State of North Rhine-Westphalia.</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":"111 ","pages":"105526"},"PeriodicalIF":9.7,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11732467/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142892847","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":"Corrigendum to Exosomal miRNA confers chemo resistance via targeting Cav1/p-gp/M2-type macrophage axis in ovarian cancer.","authors":"Pinar Kanlikilicer, Recep Bayraktar, Merve Denizli, Mohammed H Rashed, Cristina Ivan, Burcu Aslan, Rahul Mitra, Kubra Karagoz, Emine Bayraktar, Xinna Zhang, Cristian Rodriguez-Aguayo, Amr Ahmed El-Arabey, Nermin Kahraman, Seyda Baydogan, Ozgur Ozkayar, Michael L Gatza, Bulent Ozpolat, George A Calin, Anil K Sood, Gabriel Lopez-Berestein","doi":"10.1016/j.ebiom.2024.105486","DOIUrl":"10.1016/j.ebiom.2024.105486","url":null,"abstract":"","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":"111 ","pages":"105486"},"PeriodicalIF":9.7,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11653132/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142784496","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":"An ultra-early, transient interferon-associated innate immune response associates with protection from SARS-CoV-2 infection despite exposure.","authors":"Joe Fenn, Kieran Madon, Emily Conibear, Romain Derelle, Sean Nevin, Rhia Kundu, Seran Hakki, John S Tregoning, Aleksandra Koycheva, Nieves Derqui, Mica Tolosa-Wright, Jakob Jonnerby, Lulu Wang, Samuel Baldwin, Timesh D Pillay, Ryan S Thwaites, Constanta Luca, Robert Varro, Anjna Badhan, Eleanor Parker, Carolina Rosadas, Myra McClure, Richard Tedder, Graham Taylor, Ajit Lalvani","doi":"10.1016/j.ebiom.2024.105475","DOIUrl":"10.1016/j.ebiom.2024.105475","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Background: &lt;/strong&gt;A proportion of individuals exposed to respiratory viruses avoid contracting detectable infection. We tested the hypothesis that early innate immune responses associate with resistance to detectable infection in close contacts of COVID-19 cases.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;48 recently-exposed household contacts of symptomatic COVID-19 cases were recruited in London, UK between May 2020 and March 2021 through a prospective, longitudinal observational study. Blood and nose and throat swabs were collected during the acute period of index case viral shedding and longitudinally thereafter. Magnitude of SARS-CoV-2 exposure was quantified, and serial PCR and serological assays used to determine infection status of contacts. Whole-blood RNA-seq was performed and analysed to identify transcriptomic signatures of early infection and resistance to infection.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Findings: &lt;/strong&gt;24 highly-exposed household contacts became PCR-positive and seropositive whilst 24 remained persistently PCR-negative and seronegative. A 96-gene transcriptomic signature of early SARS-CoV-2 infection was identified using RNA-seq of longitudinal blood samples from PCR-positive contacts. This signature was dominated by interferon-associated genes and expression correlated positively with viral load. Elevated expression of this 96-gene signature was also observed during exposure in 25% (6/24) of persistently PCR-negative, seronegative contacts. PCR-negative contacts with elevated signature expression had higher-magnitude SARS-CoV-2 exposure compared to those with low signature expression. We validated this signature in SARS-CoV-2-infected individuals in two independent cohorts. In naturally-exposed healthcare workers (HCWs) we found that 7/58 (12%) PCR-negative HCWs exhibited elevated signature expression. Comparing gene-signature expression in SARS-CoV-2 Controlled Human Infection Model (CHIM) volunteers pre- and post-inoculation, we observed that 14 signature genes were transiently upregulated as soon as 6 hr post-inoculation in PCR-negative volunteers, while in PCR-positive volunteers gene-signature upregulation did not occur until 3 days later.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Interpretation: &lt;/strong&gt;Our interferon-associated signature of early SARS-CoV-2 infection characterises a subgroup of exposed, uninfected contacts in three independent cohorts who may have successfully aborted infection prior to induction of adaptive immunity. The earlier transient upregulation of signature genes in PCR-negative compared to PCR-positive CHIM volunteers suggests that ultra-early interferon-associated innate immune responses correlate with, and may contribute to, protection against SARS-CoV-2 infection.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Funding: &lt;/strong&gt;This work was supported by the NIHR Health Protection Research Unit in Respiratory Infections, United Kingdom, NIHR Imperial College London, United Kingdom (Grant number: NIHR200927; AL) in partnership with the UK Health Security Ag","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":"111 ","pages":"105475"},"PeriodicalIF":9.7,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11697275/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142817348","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":"Biological, as opposed to classic antipsoriatic drug or apremilast, treatment mitigates the risk of death and cardiovascular disease in psoriasis.","authors":"Khalaf Kridin, Katja Bieber, Artem Vorobyev, Eva Lotta Moderegger, Henning Olbrich, Marlene A Ludwig, Bernard Gershater, Gema Hernandez, Henner Zirpel, Diamant Thaci, Ralf J Ludwig","doi":"10.1016/j.ebiom.2024.105485","DOIUrl":"10.1016/j.ebiom.2024.105485","url":null,"abstract":"<p><strong>Background: </strong>Cardiovascular comorbidity increases morbidity and mortality in psoriasis. Systemic treatments, particularly biologics, are effective in alleviating skin and joint inflammation. Conversely, the impact of systemic therapy on cardiovascular disease risk and mortality in psoriasis remains uncertain.</p><p><strong>Methods: </strong>Impact of systemic treatments on all-cause mortality and cardiovascular disease risk in psoriasis patients' electronic health records (EHRs) from TriNetX was assessed. Treatment categories included apremilast, IL-17 inhibitors (IL-17i), IL23i, TNFi, and classic antipsoriatic drugs. Index event was the first prescription of each treatment, requiring a two-year continuous treatment with exclusion of other systemic antipsoriatic drugs. Propensity-score matching was used to improve comparability. Sensitivity analyses ensured study robustness.</p><p><strong>Findings: </strong>In descriptive analysis, all-cause mortality rates were 0.61% (classic antipsoriatics, n = 7929), 0.91% (apremilast, n = 1101), 0.00% (IL17i, n = 677), 0.81% (IL23i, n = 1242), and 0.20% (TNFi, n = 6468). Major adverse cardiac events (MACE) were documented in 8.49% (classic antipsoriatics), 5.14% (apremilast), 2.99% (IL17i), 2.09% (IL23i), and 3.74% (TNFi) EHRs. Propensity-score matching showed all-cause mortality rates of 0.23% for any biologic vs. 0.49% for classic antipsoriatics or apremilast, resulting in an HR of 2.21 (95% CI 1.21-3.71, p = 0.0073). MACE risk was also higher with classic antipsoriatics or apremilast (HR 1.66, CI 1.43-1.93, p < 0.0001). The majority of findings were consistent across all four sensitivity analyses. No significant differences in all-cause mortality or MACE risk were observed among biologics.</p><p><strong>Interpretation: </strong>Biological treatment, as opposed to classic antipsoriatic drugs or apremilast, reduces risk of death and cardiovascular disease in psoriasis. Prospective trials are required to validate these findings.</p><p><strong>Funding: </strong>DFG: EXC 2167 and LU 877/25-1. State of Schleswig Holstein: Excellence-Chair Program.</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":"111 ","pages":"105485"},"PeriodicalIF":9.7,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11665659/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142790662","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":"Safety and toxicity of Iopofosine I 131 (CLR 131) with external beam radiation therapy in recurrent or metastatic head and neck cancer: results of a phase 1 single-centre, open-label, single-arm, dose escalation and dose expansion study.","authors":"Justine Yang Bruce, Adam Burr, Randall J Kimple, David P Adam, Menggang Yu, Shari M Piaskowski, Tiffany A Glazer, Patrick Hill, Gregory K Hartig, Timothy M McCulloch, Aaron M Wieland, Diana Trask, Kate Oliver, Jarrod Longcor, Nicole Rogus-Pulia, Steve Y Cho, Bryan Bednarz, Paul M Harari","doi":"10.1016/j.ebiom.2024.105496","DOIUrl":"10.1016/j.ebiom.2024.105496","url":null,"abstract":"<p><strong>Background: </strong>Re-irradiation of recurrent head and neck cancer (HNC) is often limited by tumour adherence to critical structures and/or radiation tolerance of critical normal tissues. Iopofosine I 131 (CLR 131) is a targeted small molecular phospholipid ether (PLE) drug conjugate that delivers iodine-131 selectively to tumour cells. We conducted a phase 1, single-centre, open-label study to determine whether CLR 131 given with reduced dose of external beam radiation therapy (EBRT) would be tolerable and feasible.</p><p><strong>Methods: </strong>All participants received previous curative intent treatment with radiotherapy as primary or adjuvant treatment. Eligible participants demonstrated uptake of CLR 131 as indicated via single photon emission CT/CT (SPECT/CT) imaging following CLR 131 test dose. Participants received two therapeutic doses of CLR 131 (days 1 and 8) with SPECT/CT imaging performed to quantitate the biodistribution of CLR 131. Participants subsequently received EBRT to achieve the designated radiation dose (60-70 Gy). The primary endpoint was safety. This trial was registered with ClinicalTrials.gov, NCT04105543, and enrolment and follow-up are complete.</p><p><strong>Findings: </strong>Twelve participants completed treatment with CLR 131 and EBRT. Eight participants experienced grade 4 non-DLT haematologic toxicities (2 anaemia, 8 leukopenia, 5 thrombocytopenia) at least probably attributed to CLR 131, consistent with the expected toxicity profile. Haematologic toxicities occurred during weeks 6-8 from the first dose of CLR 131 and resolved within three weeks without sequelae. There were no treatment-related grade 3-4 non-haematologic toxicities.</p><p><strong>Interpretation: </strong>CLR 131 in combination with EBRT did not confer any safety concerns, and was tolerable in participants with recurrent/metastatic HNC. Myelosuppression was consistent with the known toxicity profile of CLR 131.</p><p><strong>Funding: </strong>National Institutes of HealthP50 DE026787, National Cancer InstituteP30 CA014520, National Institutes of Health1UL1TR002373, Cellectar, NCT04105543.</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":"111 ","pages":"105496"},"PeriodicalIF":9.7,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11700259/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142821995","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":"Polygenic risk score to the rescue of monogenic diseases? The case of epilepsy.","authors":"Jean-Madeleine De Sainte Agathe, Eric Leguern","doi":"10.1016/j.ebiom.2024.105505","DOIUrl":"10.1016/j.ebiom.2024.105505","url":null,"abstract":"","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":"111 ","pages":"105505"},"PeriodicalIF":9.7,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11733042/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142892960","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}