EBioMedicine最新文献

{"title":"The potential role of lung microbiota and lauroylcarnitine in T-cell activation associated with checkpoint inhibitor pneumonitis.","authors":"Wenyi Yu, Keqiang Wang, Yukun He, Ying Shang, Xiaoyi Hu, Xinwei Deng, Lili Zhao, Xinqian Ma, Xinlin Mu, Ran Li, Zhancheng Gao","doi":"10.1016/j.ebiom.2024.105267","DOIUrl":"10.1016/j.ebiom.2024.105267","url":null,"abstract":"<p><strong>Background: </strong>Checkpoint inhibitor pneumonitis (CIP) is a potentially fatal adverse event characterized by new pulmonary infiltrates in cancer patients receiving immune checkpoint inhibitor therapy. This study aims to explore the interplay between lung microbiota, dysregulated metabolites, and host immunity in CIP.</p><p><strong>Methods: </strong>We recruited thirteen hospitalized CIP patients, eleven idiopathic pulmonary fibrosis (IPF) patients, and ten new-onset non-small cell lung cancer patients. Bronchoalveolar lavage fluid samples were collected for 16S rRNA gene sequencing. The percentages of immune cells were determined using manual counting and flow cytometry. Interactions among microbiota, metabolites, and lymphocytes were analyzed using cultured mouse splenocytes and human T cells.</p><p><strong>Findings: </strong>Proteobacteria emerged as the dominant phylum, notably abundant in both the CIP and IPF groups. Vibrio, Halomonas, Mangrovibacter, and Salinivibrio were the predominant microbiota because of their discriminative abundance patterns. Vibrio (r = 0.72, P-adj = 0.007) and Halomonas (r = 0.65, P-adj = 0.023) demonstrated strong correlations with lymphocytes. Vibrio metschnikovii and Mangrovibacter plantisponsors were more abundant in the CIP group than in the IPF group. Lauroylcarnitine, a key intermediary metabolite co-occurring with the predominant microbiota, exhibited a potent effect on cytokine secretion by mouse and human T cells, notably enhancing IFN-γ and TNF-α production from CD4 and CD8 cells in vitro.</p><p><strong>Interpretation: </strong>Lauroylcarnitine, co-occurring with the predominant lung microbiota in CIP, could activate T cells in vitro. These findings suggest potential involvement of lung microbiota and acylcarnitine metabolism dysregulation in the pathogenesis of CIP.</p><p><strong>Funding: </strong>This work was supported by Peking University People's Hospital Scientific Research Development Funds (RDJ2022-15) and Provincial Key Clinical Specialty Capacity Building Project 2020 (Department of the Respiratory Medicine).</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/PMC11334825/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141888791","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":"Intestinal epithelium dysfunctions cause IgA deposition in the kidney glomeruli of intestine-specific Ap1m2-deficient mice.","authors":"Yusuke Kinashi, Keisuke Tanaka, Shunsuke Kimura, Masato Hirota, Seiga Komiyama, Tomoko Shindo, Akinori Hashiguchi, Daisuke Takahashi, Shinsuke Shibata, Shin-Ichiro Karaki, Hiroshi Ohno, Koji Hase","doi":"10.1016/j.ebiom.2024.105256","DOIUrl":"10.1016/j.ebiom.2024.105256","url":null,"abstract":"<p><strong>Background: </strong>Intestinal epithelial cells (IECs) serve as robust barriers against potentially hostile luminal antigens and commensal microbiota. Epithelial barrier dysfunction enhances intestinal permeability, leading to leaky gut syndrome (LGS) associated with autoimmune and chronic inflammatory disorders. However, a causal relationship between LGS and systemic disorders remains unclear. Ap1m2 encodes clathrin adaptor protein complex 1 subunit mu 2, which facilitates polarized protein trafficking toward the basolateral membrane and contributes to the establishment of epithelial barrier functions.</p><p><strong>Methods: </strong>We generated IEC-specific Ap1m2-deficient (Ap1m2^ΔIEC) mice with low intestinal barrier integrity as an LSG model and examined the systemic impact.</p><p><strong>Findings: </strong>Ap1m2^ΔIEC mice spontaneously developed IgA nephropathy (IgAN)-like features characterized by the deposition of IgA-IgG immune complexes and complement factors in the kidney glomeruli. Ap1m2 deficiency markedly enhanced aberrantly glycosylated IgA in the serum owing to downregulation and mis-sorting of polymeric immunoglobulin receptors in IECs. Furthermore, Ap1m2 deficiency caused intestinal dysbiosis by attenuating IL-22-STAT3 signaling. Intestinal dysbiosis contributed to the pathogenesis of IgAN because antibiotic treatment reduced aberrantly glycosylated IgA production and renal IgA deposition in Ap1m2^ΔIEC mice.</p><p><strong>Interpretation: </strong>IEC barrier dysfunction and subsequent dysbiosis by AP-1B deficiency provoke IgA deposition in the mouse kidney. Our findings provide experimental evidence of a pathological link between LGS and IgAN.</p><p><strong>Funding: </strong>AMED, AMED-CREST, JSPS Grants-in-Aid for Scientific Research, JST CREST, Fuji Foundation for Protein Research, and Keio University Program for the Advancement of Next Generation Research Projects.</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/PMC11338063/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141765782","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":"Approaches to scarless burn wound healing: application of 3D printed skin substitutes with dual properties of anti-infection and balancing wound hydration levels.","authors":"Shuying Chen, Yahui Xiong, Fan Yang, Yanke Hu, Jinghao Feng, Fei Zhou, Zhonghua Liu, Hengdeng Liu, Xiaogang Liu, Jingling Zhao, Zhaoqiang Zhang, Lei Chen","doi":"10.1016/j.ebiom.2024.105258","DOIUrl":"10.1016/j.ebiom.2024.105258","url":null,"abstract":"<p><strong>Background: </strong>Severe burn wounds face two primary challenges: dysregulated cellular impairment functions following infection and an unbalanced wound hydration microenvironment leading to excessive inflammation and collagen deposition. These results in hypertrophic scar contraction, causing significant deformity and disability in survivors.</p><p><strong>Methods: </strong>A three-dimensional (3D) printed double-layer hydrogel (DLH) was designed and fabricated to address the problem of scar formation after burn injury. DLH was developed using methacrylated silk fibroin (SFMA) and gelatin methacryloyl (GelMA) for the upper layer, and GelMA and hyaluronic acid methacryloyl (HAMA) for the lower layer. To combat infection, copper-epigallocatechin gallate (Cu-EGCG) was incorporated into the lower layer bioink, collectively referred to as DLS. To balance wound hydration levels, HaCaT cells were additionally encapsulated in the upper layer, designed as DLS/c.</p><p><strong>Findings: </strong>DLH demonstrated suitable porosity, appropriate mechanical properties, and excellent biocompatibility. DLS exhibited potent antimicrobial properties, exerted anti-inflammatory effects by regulating macrophage polarisation, and may enhance angiogenesis through the HIF-1α/VEGF pathway. In the DLS/c group, animal studies showed significant improvements in epidermal formation, barrier function, and epidermal hydration, accompanied by reduced inflammation. In addition, Masson's trichrome and Sirius red staining revealed that the structure and ratio of dermal collagen in DLS/c resembled that of normal skin, indicating considerable potential for scarless wound healing.</p><p><strong>Interpretation: </strong>This biomimetic matrix shows promise in addressing the challenges of burn wounds and aiming for scarless repair, with benefits such as anti-infection, epidermal hydration, biological induction, and optimised topological properties.</p><p><strong>Funding: </strong>Shown in Acknowledgements.</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/PMC11332815/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141787591","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":"Machine learning-based cluster analysis identifies four unique phenotypes of patients with degenerative cervical myelopathy with distinct clinical profiles and long-term functional and neurological outcomes.","authors":"Karlo M Pedro, Mohammed Ali Alvi, Nader Hejrati, Ayesha I Quddusi, Anoushka Singh, Michael G Fehlings","doi":"10.1016/j.ebiom.2024.105226","DOIUrl":"10.1016/j.ebiom.2024.105226","url":null,"abstract":"<p><strong>Background: </strong>Degenerative cervical myelopathy (DCM), the predominant cause of spinal cord dysfunction among adults, exhibits diverse interrelated symptoms and significant heterogeneity in clinical presentation. This study sought to use machine learning-based clustering algorithms to identify distinct patient clinical profiles and functional trajectories following surgical intervention.</p><p><strong>Methods: </strong>In this study, we applied k-means and latent profile analysis (LPA) to identify patient phenotypes, using aggregated data from three major DCM trials. The combination of Nurick score, NDI (neck disability index), neck pain, as well as motor and sensory scores facilitated clustering. Goodness-of-fit indices were used to determine the optimal cluster number. ANOVA and post hoc Tukey's test assessed outcome differences, while multinomial logistic regression identified significant predictors of group membership.</p><p><strong>Findings: </strong>A total of 1047 patients with DCM (mean [SD] age: 56.80 [11.39] years, 411 [39%] females) had complete one year outcome assessment post-surgery. Latent profile analysis identified four DCM phenotypes: \"severe multimodal impairment\" (n = 286), \"minimal impairment\" (n = 116), \"motor-dominant\" (n = 88) and \"pain-dominant\" (n = 557) groups. Each phenotype exhibited a unique symptom profile and distinct functional recovery trajectories. The \"severe multimodal impairment group\", comprising frail elderly patients, demonstrated the worst overall outcomes at one year (SF-36 PCS mean [SD]: 40.01 [9.75]; SF-36 MCS mean [SD], 46.08 [11.50]) but experienced substantial neurological recovery post-surgery (ΔmJOA mean [SD]: 3.83 [2.98]). Applying the k-means algorithm yielded a similar four-class solution. A higher frailty score and positive smoking status predicted membership in the \"severe multimodal impairment\" group (OR 1.47 [95% CI 1.07-2.02] and 1.58 [95% CI 1.25-1.99, respectively]), while undergoing anterior surgery and a longer symptom duration were associated with the \"pain-dominant\" group (OR 2.0 [95% CI 1.06-3.80] and 3.1 [95% CI 1.38-6.89], respectively).</p><p><strong>Interpretation: </strong>Unsupervised learning on multiple clinical metrics predicted distinct patient phenotypes. Symptom clustering offers a valuable framework to identify DCM subpopulations, surpassing single patient reported outcome measures like the mJOA.</p><p><strong>Funding: </strong>No funding was received for the present work. The original studies were funded by AO Spine North America.</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/PMC11283058/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141537775","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":"Effect of ultrasound-mediated blood-spinal cord barrier opening on survival and motor function in females in an amyotrophic lateral sclerosis mouse model.","authors":"Anne-Sophie Montero, Ilyes Aliouat, Matthieu Ribon, Michael Canney, Lauriane Goldwirt, Samia Mourah, Félix Berriat, Christian S Lobsiger, Pierre-François Pradat, François Salachas, Gaëlle Bruneteau, Alexandre Carpentier, Séverine Boillée","doi":"10.1016/j.ebiom.2024.105235","DOIUrl":"10.1016/j.ebiom.2024.105235","url":null,"abstract":"<p><strong>Background: </strong>Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by a progressive loss of motor neurons. The limited efficacy of recent therapies in clinical development may be linked to lack of drug penetration to the affected motor neurons due to the blood-brain barrier (BBB) and blood-spinal cord barrier (BSCB).</p><p><strong>Methods: </strong>In this work, the safety and efficacy of repeated short transient opening of the BSCB by low intensity pulsed ultrasound (US, sonication) was studied in females of an ALS mouse model (B6.Cg-Tg(SOD1∗G93A)1Gur/J). The BSCB was disrupted using a 1 MHz ultrasound transducer coupled to the spinal cord, with and without injection of insulin-like growth factor 1 (IGF1), a neurotrophic factor that has previously shown efficacy in ALS models.</p><p><strong>Findings: </strong>Results in wild-type (WT) animals demonstrated that the BSCB can be safely disrupted and IGF1 concentrations significantly enhanced after a single session of transient BSCB disruption (176 ± 32 μg/g vs. 0.16 ± 0.008 μg/g, p < 0.0001). Five repeated weekly US sessions performed in female ALS mice demonstrated a survival advantage in mice treated with IGF1 and US (US IGF1) compared to treatment with IGF1 alone (176 vs. 166 days, p = 0.0038). Surprisingly, this survival advantage was also present in mice treated with US alone vs. untreated mice (178.5 vs. 166.5 days, p = 0.0061). Muscle strength did not show difference among the groups. Analysis of glial cell immunoreactivity and microglial transcriptome showing reduced cell proliferation pathways, in addition to lymphocyte infiltration, suggested that the beneficial effect of US or US IGF1 could act through immune cell modulation.</p><p><strong>Interpretation: </strong>These results show the first step towards a possible beneficial impact of transient BSCB opening for ALS therapy and suggest implication of immune cells.</p><p><strong>Funding: </strong>Fondation pour la Recherche Médicale (FRM). Investissements d'avenirANR-10-IAIHU-06, Société Française de Neurochirurgie (SFNC), Fond d'étude et de Recherche du Corps Medical (FERCM), Aide à la Recherche des Maladies du Cerveau (ARMC), SLA Fondation Recherche (SLAFR), French Ministry for High Education and Research (MENR), Carthera, Laboratoire de Recherche en Technologies Chirurgicales Avancées (LRTCA).</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/PMC11284947/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141598924","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":"Identifying the earliest-occurring clinically targetable precursors of late-onset Alzheimer's disease.","authors":"Bruce M Cohen, Kai-Christian Sonntag","doi":"10.1016/j.ebiom.2024.105238","DOIUrl":"10.1016/j.ebiom.2024.105238","url":null,"abstract":"<p><p>Most cases of Alzheimer's disease (AD) are late-onset dementias (LOAD). However, research on AD is predominantly of early-onset disease (EOAD). The determinants of EOAD, gene variants of APP and presenilin proteins, are not the basic precursors of LOAD. Rather, multiple other genes and associated cellular processes underlie risk for LOAD. These determinants could be modified in individuals at risk for LOAD well before signs and symptoms appear. Studying brain cells produced from patient-derived induced-pluripotent-stem-cells (iPSC), in culture, will be instrumental in developing such interventions. This paper summarises evidence accrued from iPSC culture models identifying the earliest occurring clinically targetable determinants of LOAD. Results obtained and replicated, thus far, suggest that abnormalities of bioenergetics, lipid metabolism, digestive organelle function and inflammatory activity are primary processes underlying LOAD. The application of cell culture platforms will become increasingly important in research and also on LOAD detection, assessment, and treatment in the years ahead.</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/PMC11284560/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141603461","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":"Intestinal microbiota composition is predictive of radiotherapy-induced acute gastrointestinal toxicity in prostate cancer patients.","authors":"Jacopo Iacovacci, Mara Serena Serafini, Barbara Avuzzi, Fabio Badenchini, Alessandro Cicchetti, Andrea Devecchi, Michela Dispinzieri, Valentina Doldi, Tommaso Giandini, Eliana Gioscio, Elisa Mancinelli, Barbara Noris Chiorda, Ester Orlandi, Federica Palorini, Luca Possenti, Miguel Reis Ferreira, Sergio Villa, Nadia Zaffaroni, Loris De Cecco, Riccardo Valdagni, Tiziana Rancati","doi":"10.1016/j.ebiom.2024.105246","DOIUrl":"10.1016/j.ebiom.2024.105246","url":null,"abstract":"<p><strong>Background: </strong>The search for factors beyond the radiotherapy dose that could identify patients more at risk of developing radio-induced toxicity is essential to establish personalised treatment protocols for improving the quality-of-life of survivors. To investigate the role of the intestinal microbiota in the development of radiotherapy-induced gastrointestinal toxicity, the MicroLearner observational cohort study characterised the intestinal microbiota of 136 (discovery) and 79 (validation) consecutive prostate cancer patients at baseline radiotherapy.</p><p><strong>Methods: </strong>Gastrointestinal toxicity was assessed weekly during RT using CTCAE. An average grade >1.3 over time points was used to identify patients suffering from persistent acute toxicity (endpoint). The microbiota of patients was quantified from the baseline faecal samples using 16S rRNA gene sequencing technology and the Ion Reporter metagenomic pipeline. Statistical techniques and computational and machine learning tools were used to extract, functionally characterise, and predict core features of the bacterial communities of patients who developed acute gastrointestinal toxicity.</p><p><strong>Findings: </strong>Analysis of the core bacterial composition in the discovery cohort revealed a cluster of patients significantly enriched for toxicity, displaying a toxicity rate of 60%. Based on selected high-risk microbiota compositional features, we developed a clinical decision tree that could effectively predict the risk of toxicity based on the relative abundance of genera Faecalibacterium, Bacteroides, Parabacteroides, Alistipes, Prevotella and Phascolarctobacterium both in internal and external validation cohorts.</p><p><strong>Interpretation: </strong>We provide evidence showing that intestinal bacteria profiling from baseline faecal samples can be effectively used in the clinic to improve the pre-radiotherapy assessment of gastrointestinal toxicity risk in prostate cancer patients.</p><p><strong>Funding: </strong>Italian Ministry of Health (Promotion of Institutional Research INT-year 2016, 5 × 1000, Ricerca Corrente funds). Fondazione Regionale per la Ricerca Biomedica (ID 2721017). AIRC (IG 21479).</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/PMC11314862/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141727027","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":"Blood DNA methylation in post-acute sequelae of COVID-19 (PASC): a prospective cohort study.","authors":"Joseph Balnis, Andy Madrid, Lisa A Drake, Rachel Vancavage, Anupama Tiwari, Vraj J Patel, Ramon Bossardi Ramos, John J Schwarz, Recai Yucel, Harold A Singer, Reid S Alisch, Ariel Jaitovich","doi":"10.1016/j.ebiom.2024.105251","DOIUrl":"10.1016/j.ebiom.2024.105251","url":null,"abstract":"<p><strong>Background: </strong>DNA methylation integrates environmental signals with transcriptional programs. COVID-19 infection induces changes in the host methylome. While post-acute sequelae of COVID-19 (PASC) is a long-term complication of acute illness, its association with DNA methylation is unknown. No universal blood marker of PASC, superseding single organ dysfunctions, has yet been identified.</p><p><strong>Methods: </strong>In this single centre prospective cohort study, PASC, post-COVID without PASC, and healthy participants were enrolled to investigate their symptoms association with peripheral blood DNA methylation data generated with state-of-the-art whole genome sequencing. PASC-induced quality-of-life deterioration was scored with a validated instrument, SF-36. Analyses were conducted to identify potential functional roles of differentially methylated loci, and machine learning algorithms were used to resolve PASC severity.</p><p><strong>Findings: </strong>103 patients with PASC (22.3% male, 77.7% female), 15 patients with previous COVID-19 infection but no PASC (40.0% male, 60.0% female), and 27 healthy volunteers (48.1% male, 51.9% female) were enrolled. Whole genome methylation sequencing revealed 39 differentially methylated regions (DMRs) specific to PASC, each harbouring an average of 15 consecutive positions, that differentiate patients with PASC from the two control groups. Motif analyses of PASC-regulated DMRs identify binding domains for transcription factors regulating circadian rhythm and others. Some DMRs annotated to protein coding genes were associated with changes of RNA expression. Machine learning support vector algorithm and random forest hierarchical clustering reveal 28 unique differentially methylated positions (DMPs) in the genome discriminating patients with better and worse quality of life.</p><p><strong>Interpretation: </strong>Blood DNA methylation levels identify PASC, stratify PASC severity, and suggest that DNA motifs are targeted by circadian rhythm-regulating pathways in PASC.</p><p><strong>Funding: </strong>This project has been funded by the following agencies: NIH-AI173035 (A. Jaitovich and R. Alisch); and NIH-AG066179 (R. Alisch).</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/PMC11286994/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141723289","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":"Human effector CD8⁺ T cells with an activated and exhausted-like phenotype control tumour growth in vivo in a humanized tumour model.","authors":"Juliane Mietz, Meike Kaulfuss, Lukas Egli, Lennart Opitz, Christian Münz, Obinna Chijioke","doi":"10.1016/j.ebiom.2024.105240","DOIUrl":"10.1016/j.ebiom.2024.105240","url":null,"abstract":"<p><strong>Background: </strong>Humanized tumour models could be particularly valuable for cancer immunotherapy research, as they may better reflect human-specific aspects of the interfaces between tumour and immune system of human cancer. However, endogenous antitumour immunity in humanized models is still largely undefined.</p><p><strong>Methods: </strong>We established an autologous humanized mouse tumour model by using NSG mice reconstituted with human immune cells from hematopoietic progenitors and tumours generated from transformed autologous human B cells. We demonstrate growth of solid lymphoid tumours after subcutaneous implantation, infiltration by endogenous human immune cells and immunocompetence of the model.</p><p><strong>Findings: </strong>We found human T cell subsets described in human cancer, including progenitor exhausted (T_pex), terminally exhausted (T_ex-term) and tissue-resident (T_RM) cells in tumour-bearing humanized mice with accumulation of T_ex-term and T_RM in the tumour. In addition, we identified tumour-reactive CD8⁺ T cells through expression of CD137. This subpopulation of de novo arising human CD137⁺ CD8⁺ T cells displayed a highly proliferative, fully activated effector and exhausted-like phenotype with enhanced expression of activation and exhaustion markers like PD-1, CD39, CD160, TIM-3, TIGIT and TOX, the senescence marker CD57 (B3GAT1) and cytolytic effector molecules such as PRF1, GZMH and NKG7. Moreover, these CD137⁺ CD8⁺ T cells exhibited tumour-specific clonal expansion and presented signature overlap with tumour-reactive CD8⁺ T cells described in human cancer. We demonstrate superior anticancer activity of this activated and exhausted-like human CD8⁺ T cell subset by adoptive transfer experiments using recipients bearing autologous human tumours. Mice adoptively transferred with CD137⁺ CD8⁺ T cells showed reduced tumour growth and higher CD8⁺ T cell tumour infiltration, correlating with control of human tumours.</p><p><strong>Interpretation: </strong>We established an immunocompetent humanized tumour model, providing a tool for immunotherapy research and defined effective anticancer activity of human effector CD8⁺ T cells with an activated and exhausted-like phenotype, supporting clinical exploration of such cells in adoptive T cell therapies.</p><p><strong>Funding: </strong>Swiss Cancer Research foundation.</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/PMC11296066/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141579260","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":"Distinct neurodevelopmental and epileptic phenotypes associated with gain- and loss-of-function GABRB2 variants.","authors":"Nazanin Azarinejad Mohammadi, Philip Kiær Ahring, Vivian Wan Yu Liao, Han Chow Chua, Sebastián Ortiz de la Rosa, Katrine Marie Johannesen, Yael Michaeli-Yossef, Aline Vincent-Devulder, Catherine Meridda, Ange-Line Bruel, Alessandra Rossi, Chirag Patel, Joerg Klepper, Paolo Bonanni, Sara Minghetti, Marina Trivisano, Nicola Specchio, David Amor, Stéphane Auvin, Sarah Baer, Pierre Meyer, Mathieu Milh, Vincenzo Salpietro, Reza Maroofian, Johannes R Lemke, Sarah Weckhuysen, Palle Christophersen, Guido Rubboli, Mary Chebib, Anders A Jensen, Nathan L Absalom, Rikke Steensbjerre Møller","doi":"10.1016/j.ebiom.2024.105236","DOIUrl":"10.1016/j.ebiom.2024.105236","url":null,"abstract":"<p><strong>Background: </strong>Variants in GABRB2, encoding the β2 subunit of the γ-aminobutyric acid type A (GABA_A) receptor, can result in a diverse range of conditions, ranging from febrile seizures to severe developmental and epileptic encephalopathies. However, the mechanisms underlying the risk of developing milder vs more severe forms of disorder remain unclear. In this study, we conducted a comprehensive genotype-phenotype correlation analysis in a cohort of individuals with GABRB2 variants.</p><p><strong>Methods: </strong>Genetic and electroclinical data of 42 individuals harbouring 26 different GABRB2 variants were collected and accompanied by electrophysiological analysis of the effects of the variants on receptor function.</p><p><strong>Findings: </strong>Electrophysiological assessments of α1β2γ2 receptors revealed that 25/26 variants caused dysfunction to core receptor properties such as GABA sensitivity. Of these, 17 resulted in gain-of-function (GOF) while eight yielded loss-of-function traits (LOF). Genotype-phenotype correlation analysis revealed that individuals harbouring GOF variants suffered from severe developmental delay/intellectual disability (DD/ID, 74%), movement disorders such as dystonia or dyskinesia (59%), microcephaly (50%) and high risk of early mortality (26%). Conversely, LOF variants were associated with milder disease manifestations. Individuals with these variants typically exhibited fever-triggered seizures (92%), milder degrees of DD/ID (85%), and maintained ambulatory function (85%). Notably, severe movement disorders or microcephaly were not reported in individuals with loss-of-function variants.</p><p><strong>Interpretation: </strong>The data reveals that genetic variants in GABRB2 can lead to both gain and loss-of-function, and this divergence is correlated with distinct disease manifestations. Utilising this information, we constructed a diagnostic flowchart that aids in predicting the pathogenicity of recently identified variants by considering clinical phenotypes.</p><p><strong>Funding: </strong>This work was funded by the Australian National Health & Medical Research Council, the Novo Nordisk Foundation and The Lundbeck Foundation.</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/PMC11296288/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141598923","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}