EBioMedicine最新文献

{"title":"Prognostic clinical and biological markers for amyotrophic lateral sclerosis disease progression: validation and implications for clinical trial design and analysis.","authors":"Michael Benatar, Eric A Macklin, Andrea Malaspina, Mary-Louise Rogers, Eran Hornstein, Vittoria Lombardi, Danielle Renfrey, Stephanie Shepheard, Iddo Magen, Yahel Cohen, Volkan Granit, Jeffrey M Statland, Jeannine M Heckmann, Rosa Rademakers, Caroline A McHutchison, Leonard Petrucelli, Corey T McMillan, Joanne Wuu","doi":"10.1016/j.ebiom.2024.105323","DOIUrl":"10.1016/j.ebiom.2024.105323","url":null,"abstract":"<p><strong>Background: </strong>With increasing recognition of the value of incorporating prognostic markers into amyotrophic lateral sclerosis (ALS) trial design and analysis plans, there is a pressing need to understand which among the prevailing clinical and biochemical markers have real value, and how they can be optimally used.</p><p><strong>Methods: </strong>A subset of patients with ALS recruited through the multi-center Phenotype-Genotype-Biomarker study (clinicaltrials.gov: NCT02327845) was identified as \"trial-like\" based on meeting common trial eligibility criteria. Clinical phenotyping was performed by evaluators trained in relevant assessments. Serum neurofilament light (NfL) and phosphorylated neurofilament heavy (pNfH), urinary p75^ECD, plasma microRNA-181, and an array of biochemical and clinical measures were evaluated for their prognostic value. Associations with functional progression were estimated by random-slopes mixed models of ALS functional rating scale-revised (ALSFRS-R) score. Associations with survival were estimated by log-rank test and Cox proportional hazards regression. Potential sample size savings from adjusting for given biomarkers in a hypothetical trial were estimated.</p><p><strong>Findings: </strong>Baseline serum NfL is a powerful prognostic biomarker, predicting survival and ALSFRS-R rate of decline. Serum NfL <40 pg/mL and >100 pg/mL correspond to future ALSFRS-R slopes of ∼0.5 and ∼1.5 points/month, respectively. Serum NfL also adds value to the best available clinical predictors, encapsulated by the European Network to Cure ALS (ENCALS) predictor score. In models of functional decline, the addition of NfL yields ∼25% sample size saving above those achieved by inclusion of either clinical predictors or ENCALS score alone. The prognostic value of serum pNfH, urinary p75^ECD, and plasma miR-181ab is more limited.</p><p><strong>Interpretation: </strong>Among the multitude of biomarkers considered, only blood NfL adds value to the ENCALS prediction model and should be incorporated into analysis plans for all ongoing and future ALS trials. Defined thresholds of NfL might also be used in trial design, for enrichment or stratified randomisation, to improve trial efficiency.</p><p><strong>Funding: </strong>NIH (U01-NS107027, U54-NS092091). ALSA (16-TACL-242).</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":null,"pages":null},"PeriodicalIF":9.7,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11415817/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142282136","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 \"The significance of recurrent de novo amino acid substitutions that emerged during chronic SARS-CoV-2 infection: an observational study\" [eBioMedicine, 2024;107:105273].","authors":"Jonathan Daniel Ip, Wing-Ming Chu, Wan-Mui Chan, Allen Wing-Ho Chu, Rhoda Cheuk-Ying Leung, Qi Peng, Anthony Raymond Tam, Brian Pui-Chun Chan, Jian-Piao Cai, Kwok-Yung Yuen, Kin-Hang Kok, Yi Shi, Ivan Fan-Ngai Hung, Kelvin Kai-Wang To","doi":"10.1016/j.ebiom.2024.105371","DOIUrl":"10.1016/j.ebiom.2024.105371","url":null,"abstract":"","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":null,"pages":null},"PeriodicalIF":9.7,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11462265/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142343694","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":"Profiling steroid hormone landscape of bladder cancer reveals depletion of intratumoural androgens to castration levels: a cross-sectional study.","authors":"Kimmo Kettunen, Julia Mathlin, Tarja Lamminen, Asta Laiho, Merja R Häkkinen, Seppo Auriola, Laura L Elo, Peter J Boström, Matti Poutanen, Pekka Taimen","doi":"10.1016/j.ebiom.2024.105359","DOIUrl":"10.1016/j.ebiom.2024.105359","url":null,"abstract":"<p><strong>Background: </strong>Bladder cancer is a highly over-represented disease in males. The involvement of sex steroids in bladder carcinogenesis and the utilisation of steroid hormone action as a therapeutic target have been frequently proposed. However, the intratumoural steroid milieu remains unclear.</p><p><strong>Methods: </strong>We used mass spectrometry and transcriptomic profiling to determine the levels of 23 steroid hormones and the expression of steroidogenic enzymes in primary tumours from patients who underwent transurethral resection (n = 24), and tumours and adjacent morphologically benign bladder tissues from treatment-naïve patients, who underwent radical cystectomy (n = 20). The corresponding steroids were determined from the patients' sera.</p><p><strong>Findings: </strong>Our results show that both bladder tumours and non-tumour tissues are androgen-poor, with DHT being virtually unquantifiable and testosterone at castration levels. Intratumoural enzymes that inactivate potent androgens (e.g., HSD17B2) exhibited similar tumour aggressiveness-linked downregulation, as reported in advanced forms of classical steroid-dependent cancers, whereas there was little change in the corresponding activating enzymes. Finally, our results suggest cancer aggressiveness-linked dissimilarities in steroid profiles; the patients with overall low circulating steroid levels and those with an association between androgen receptor expression and intratumoural testosterone levels in place had fewer recurrences than the rest.</p><p><strong>Interpretation: </strong>By revealing the steroid landscape of bladder cancer, our study not only underscores the androgen-poor nature of the malignancy but also identifies potential alterations in steroid profiles that are linked to disease aggressiveness.</p><p><strong>Funding: </strong>The Cancer Foundation Finland, the Finnish State Research Funding (VTR).</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":null,"pages":null},"PeriodicalIF":9.7,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11459583/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142343700","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":"Convergence of SARS-CoV-2 spike antibody levels to a population immune setpoint.","authors":"Eric J Nilles, Kathryn Roberts, Michael de St Aubin, Helen Mayfield, Angela Cadavid Restrepo, Salome Garnier, Gabriela Abdalla, Marie Caroline Etienne, William Duke, Devan Dumas, Petr Jarolim, Timothy Oasan, Farah Peña, Beatriz Lopez, Lucia de la Cruz, Isaac Miguel Sanchez, Kristy Murray, Margaret Baldwin, Ronald Skewes-Ramm, Cecilia Then Paulino, Colleen L Lau, Adam Kucharski","doi":"10.1016/j.ebiom.2024.105319","DOIUrl":"10.1016/j.ebiom.2024.105319","url":null,"abstract":"<p><strong>Background: </strong>Individual immune responses to SARS-CoV-2 are well-studied, while the combined effect of these responses on population-level immune dynamics remains poorly understood. Given the key role of population immunity on pathogen transmission, delineation of the factors that drive population immune evolution has critical public health implications.</p><p><strong>Methods: </strong>We enrolled individuals 5 years and older selected using a multistage cluster survey approach in the Northwest and Southeast of the Dominican Republic. Paired blood samples were collected mid-pandemic (Aug 2021) and late pandemic (Nov 2022). We measured serum pan-immunoglobulin antibodies against the SARS-CoV-2 spike protein. Generalized Additive Models (GAMs) and random forest models were used to analyze the relationship between changes in antibody levels and various predictor variables. Principal component analysis and partial dependence plots further explored the relationships between predictors and antibody changes.</p><p><strong>Findings: </strong>We found a transformation in the distribution of antibody levels from an irregular to a normalized single peak Gaussian distribution that was driven by titre-dependent boosting. This led to the convergence of antibody levels around a common immune setpoint, irrespective of baseline titres and vaccination profile.</p><p><strong>Interpretation: </strong>Our results suggest that titre-dependent kinetics driven by widespread transmission direct the evolution of population immunity in a consistent manner. These findings have implications for targeted vaccination strategies and improved modeling of future transmission, providing a preliminary blueprint for understanding population immune dynamics that could guide public health and vaccine policy for SARS-CoV-2 and potentially other pathogens.</p><p><strong>Funding: </strong>The study was primarily funded by the Centers for Disease Control and Prevention grant U01GH002238 (EN). Salary support was provided by Wellcome Trust grant 206250/Z/17/Z (AK) and the Australian National Health and Medical Research Council Investigator grant APP1158469 (CLL).</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":null,"pages":null},"PeriodicalIF":9.7,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11404201/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142132155","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":"What defines hypervirulent Klebsiella pneumoniae?","authors":"Thomas D Stanton, Kelly L Wyres","doi":"10.1016/j.ebiom.2024.105331","DOIUrl":"10.1016/j.ebiom.2024.105331","url":null,"abstract":"","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":null,"pages":null},"PeriodicalIF":9.7,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11414540/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142282148","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":"Clinical and research application of fluid biomarkers in autosomal dominant Alzheimer's disease and Down syndrome.","authors":"María Carmona-Iragui, Antoinette O'Connor, Jorge Llibre-Guerra, Patrick Lao, Nicholas J Ashton, Juan Fortea, Raquel Sánchez-Valle","doi":"10.1016/j.ebiom.2024.105327","DOIUrl":"10.1016/j.ebiom.2024.105327","url":null,"abstract":"<p><p>Autosomal dominant Alzheimer's disease (ADAD) and Down syndrome (DS) constitute genetic forms of Alzheimer's disease (AD). The study of these forms has been crucial in understanding the biomarker changes and disease progression, notably in advancing our knowledge of the natural history of AD. However, some specific characteristics of biomarkers in genetically determined forms and, most importantly, the near full penetrance and predictability of disease onset lead to a very different context of use for biomarkers in these populations. This article delves into the similarities and differences in biomarker profiles between genetically determined AD and sporadic cases, discussing the implications for research and clinical practice. It also emphasizes the need to account for factors that may affect biomarker reliability differently in genetically determined AD. Enhancing our understanding of the disease will pave the way for more personalized therapeutic approaches for affected individuals.</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":null,"pages":null},"PeriodicalIF":9.7,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142375257","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Insights into the use of biomarkers in clinical trials in Alzheimer's disease.","authors":"Tharick A Pascoal, Cristiano S Aguzzoli, Firoza Z Lussier, Lucía Crivelli, Claudia K Suemoto, Juan Fortea, Pedro Rosa-Neto, Eduardo R Zimmer, Pamela C L Ferreira, Bruna Bellaver","doi":"10.1016/j.ebiom.2024.105322","DOIUrl":"10.1016/j.ebiom.2024.105322","url":null,"abstract":"<p><p>Biomarkers have been instrumental in population selection and disease monitoring in clinical trials of recently FDA-approved drugs targeting amyloid-β to slow the progression of Alzheimer's disease (AD). As new therapeutic strategies and biomarker techniques emerge, the importance of biomarkers in drug development is growing exponentially. In this emerging landscape, biomarkers are expected to serve a wide range of contexts of use in clinical trials focusing on AD and related dementias. The joint FDA-NIH BEST (Biomarkers, EndpointS, and other Tools) framework provides standardised terminology to facilitate communication among stakeholders in this increasingly complex field. This review explores various applications of biomarkers relevant to AD clinical trials, using the BEST resource as a reference. For simplicity, we predominantly provide contextual characterizations of biomarkers use from the perspective of drugs targeting amyloid-β and tau proteins. However, general definitions and concepts can be extrapolated to other targets.</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":null,"pages":null},"PeriodicalIF":9.7,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142375259","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Clinical phenotypes of DCM and their implications in post-surgery recovery.","authors":"Fauziyya Muhammad, Zachary A Smith","doi":"10.1016/j.ebiom.2024.105357","DOIUrl":"10.1016/j.ebiom.2024.105357","url":null,"abstract":"","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":null,"pages":null},"PeriodicalIF":9.7,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11426392/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142282131","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":"Immune correlates analysis of the Imbokodo (HVTN 705/HPX2008) efficacy trial of a mosaic HIV-1 vaccine regimen evaluated in Southern African people assigned female sex at birth: a two-phase case-control study.","authors":"Avi Kenny, Janine van Duijn, One Dintwe, Jack Heptinstall, Randy Burnham, Sheetal Sawant, Lu Zhang, Dieter Mielke, Sharon Khuzwayo, Faatima Laher Omar, Sherry Stanfield-Oakley, Taylor Keyes, Brooke Dunn, Derrick Goodman, Youyi Fong, David Benkeser, Rodger Zou, John Hural, Ollivier Hyrien, Michal Juraska, Alex Luedtke, Lars van der Laan, Elena E Giorgi, Craig Magaret, Lindsay N Carpp, Laura Pattacini, Tom van de Kerkhof, Bette Korber, Wouter Willems, Leigh H Fisher, Hanneke Schuitemaker, Edith Swann, James G Kublin, Maria G Pau, Susan Buchbinder, Frank Tomaka, Steven Nijs, Ludo Lavreys, Huub C Gelderblom, Lawrence Corey, Kathryn Mngadi, Glenda E Gray, Erica Borducchi, Jenny Hendriks, Kelly E Seaton, Susan Zolla-Pazner, Dan H Barouch, Guido Ferrari, Stephen C De Rosa, M Juliana McElrath, Erica Andersen-Nissen, Daniel J Stieh, Georgia D Tomaras, Peter B Gilbert","doi":"10.1016/j.ebiom.2024.105320","DOIUrl":"10.1016/j.ebiom.2024.105320","url":null,"abstract":"<p><strong>Background: </strong>The HVTN 705 Imbokodo trial of 2636 people without HIV and assigned female sex at birth, conducted in southern Africa, evaluated a heterologous HIV-1 vaccine regimen: mosaic adenovirus 26-based vaccine (Ad26.Mos4.HIV) at Months 0, 3, 6, 12 and alum-adjuvanted clade C gp140 at Months 6, 12. Per-protocol vaccine efficacy (VE) against HIV-1 diagnosis from seven to 24 months was 14.1% (95% CI: -22.0% to 39.5%). Immune correlates analysis was performed for markers selected based on prior evidence in efficacy trials and/or nonhuman primate models.</p><p><strong>Methods: </strong>Humoral and cellular immune response markers at Month 7 were evaluated as immune correlates of risk and of protection in a breakthrough case-control cohort (n = 52 cases, 246 non-cases). Primary markers were IgG binding to vaccine-strain gp140, IgG3 binding to diverse Env antigens (IgG3 Env breadth), IgG3 binding to diverse V1V2 antigens (IgG3 V1V2 breadth), antibody-dependent phagocytosis against the vaccine-strain gp140, Env-specific CD4+ and CD8+ T-cell responses, and multi-epitope functions.</p><p><strong>Findings: </strong>No immune markers were statistically significant correlates of risk. IgG3 V1V2 breadth trended toward an inverse association: hazard ratio 0.70 (95% CI: 0.36 to 1.35; p = 0.29) per 10-fold increase and 0.51 (95% CI: 0.21 to 1.24; p = 0.14) in a Cox model with all primary markers. The VE estimate was 11.8% (95% CI: -17.9% to 34.0%) at all IgG3 V1V2 breadth values below 667 weighted geometric mean net MFI; just above this value, the VE estimate sharply increased to 62.6% (95% CI: -17.9% to 89.6%), and further increased to 80.9% (95% CI: -17.9% to 99.5%) at 1471 MFI, the 95th percentile of the marker distribution. Mediation analysis yielded a VE of 35.7% (95% CI: 15.0% to 51.3%) attributable to the vaccine's impact on this marker.</p><p><strong>Interpretation: </strong>The trend in association of greater IgG3 V1V2 antibody breadth with lower likelihood of HIV acquisition is consistent with the identification of antibodies against V1V2 as immune correlates in three other HIV vaccine efficacy trials and suggests that a greater emphasis should be placed on studying this region in the HIV-1 envelope as a vaccine immunogen.</p><p><strong>Funding: </strong>National Institute of Allergy and Infectious Diseases and Janssen Vaccines & Prevention BV.</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":null,"pages":null},"PeriodicalIF":9.7,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11404224/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142139630","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 synergistic unsupervised-supervised learning approach for data-driven and clinically applicable patient phenotyping.","authors":"Mert Karabacak, Konstantinos Margetis","doi":"10.1016/j.ebiom.2024.105358","DOIUrl":"10.1016/j.ebiom.2024.105358","url":null,"abstract":"","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":null,"pages":null},"PeriodicalIF":9.7,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11459054/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142282127","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}