EBioMedicine最新文献

{"title":"SLC7A9 suppression increases chemosensitivity by inducing ferroptosis via the inhibition of cystine transport in gastric cancer.","authors":"Haoran Feng, Junxian Yu, Zhuoqing Xu, Qingqing Sang, Fangyuan Li, Mengdi Chen, Yunqin Chen, Beiqin Yu, Nan Zhu, Jiazeng Xia, Changyu He, Junyi Hou, Xiongyan Wu, Chao Yan, Zhenggang Zhu, Liping Su, Jianfang Li, Wentao Dai, Yuan-Yuan Li, Bingya Liu","doi":"10.1016/j.ebiom.2024.105375","DOIUrl":"10.1016/j.ebiom.2024.105375","url":null,"abstract":"<p><strong>Background: </strong>SLC7A9 is responsible for the exchange of dibasic amino acids and cystine (influx) for neutral amino acids (efflux). Cystine/cysteine transport is related to ferroptosis.</p><p><strong>Methods: </strong>Sanger sequencing detected TP53 status of cancer cells. Transcriptomic sequencing and untargeted metabolome profiling were used to identify differentially expressed genes and metabolites, respectively, upon SLC7A9 overexpression. CCK8, cell clonality, and EdU assays were used to observe cell proliferation. Cystine probes, glutathione (GSH) probes, and lipid ROS probes were used to examine cystine, GSH, and lipid ROS levels. ¹³C metabolic flow assays were used to monitor cellular cystine and GSH metabolism. Patient-derived organoids (PDO), immunocompetent MFC mice allograft models and patient-derived xenograft (PDX) models were used to evaluate SLC7A9 impact on chemotherapeutic response and to observe therapeutic effect of SLC7A9 knockdown.</p><p><strong>Findings: </strong>Elevated SLC7A9 expression levels in gastric cancer cells were attributed to p53 loss. SLC7A9 knockdown suppressed the proliferation and increased the chemotherapy sensitivity of the cells. Chemotherapy was more effective in PDX and immunocompetent mice models upon SLC7A9 knockdown. Differentially expressed genes and metabolites between the SLC7A9 overexpression and control groups were associated with ferroptosis and GSH metabolism. SLC7A9 knockdown reduced cystine transport into cells, hampered intracellular cystine and GSH metabolic flow, decreased GSH synthesis, and increased lipid ROS levels in gastric cancer cells. Erastin was more effective at inducing ferroptosis in PDO and PDX models upon SLC7A9 knockdown.</p><p><strong>Interpretation: </strong>SLC7A9 promotes gastric cancer progression by acting as a suppressor of ferroptosis, independent of SLC7A11, which is negatively regulated by p53.</p><p><strong>Funding: </strong>This work was supported by National Natural Science Foundation of China, Innovation Promotion Program of NHC and Shanghai Key Labs SIBPT, and Shanghai Academy of Science & Technology.</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":null,"pages":null},"PeriodicalIF":9.7,"publicationDate":"2024-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11536348/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142497100","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":"Detection and staging of Alzheimer's disease by plasma pTau217 on a high throughput immunoassay platform.","authors":"Azadeh Feizpour, James David Doecke, Vincent Doré, Natasha Krishnadas, Kun Huang, Pierrick Bourgeat, Simon Matthew Laws, Christopher Fowler, Joanne Robertson, Lucy Mackintosh, Scott Ayton, Ralph Martins, Stephanie Ruth Rainey-Smith, Kevin Taddei, Larry Ward, Eddie Stage, Anthony Wilson Bannon, Colin Louis Masters, Jurgen Fripp, Victor Luis Villemagne, Christopher Cleon Rowe","doi":"10.1016/j.ebiom.2024.105405","DOIUrl":"10.1016/j.ebiom.2024.105405","url":null,"abstract":"<p><strong>Background: </strong>Plasma phospho-tau 217 (pTau217) assays can accurately detect Alzheimer's disease (AD) pathology, but clinical application is limited by the need for specialised equipment. This study tests the performance of a plasma pTau217 assay performed on the Lumipulse-G® platform, that is in widespread clinical use, for selecting patients for therapy based on β-amyloid (Aβ) status and tau staging.</p><p><strong>Methods: </strong>Participants included 388 individuals with ¹⁸F-NAV4694 Aβ-PET and ¹⁸F-MK6240 tau-PET. Association of pTau217 with PET was examined using Spearman's correlation. Discriminative performance for Aβ and tau PET status as well as tau staging was assessed using Receiver Operating Characteristic analysis.</p><p><strong>Findings: </strong>Plasma pTau217 had a high correlation with both Aβ Centiloid (r = 0.76) and tau SUVR_{meta-temporal} (r = 0.78). Area under curve (AUC) was 0.93 for Aβ- vs Aβ+ and 0.94 for tau- vs tau+. Applying one threshold (Youden's index), pTau217 was 87% accurate in classification of participants to Aβ- vs Aβ+. Applying two thresholds to classify participants into Low, Indeterminate, and High zones, 17.8% had Indeterminate results and among Low/High zone participants, 92% were correctly classified as Aβ- or Aβ+. The assay accurately discriminated moderate/high neocortical tau from no tau or tau limited to mesial-temporal lobe (AUC 0.97) and high neocortical tau from all others (AUC 0.94).</p><p><strong>Interpretation: </strong>Plasma pTau217, measured by the widely-available, fully-automated Lumipulse®, was a strong predictor of both Aβ and tau PET status and demonstrated strong predictive power in identifying individuals likely to benefit the most from anti-Aβ treatments.</p><p><strong>Funding: </strong>NHMRC grants 1132604, 1140853, 1152623 and AbbVie.</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":null,"pages":null},"PeriodicalIF":9.7,"publicationDate":"2024-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11536028/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142497078","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":"Transmission of highly virulent CXCR4 tropic HIV-1 through the mucosal route in an individual with a wild-type CCR5 genotype.","authors":"Manukumar Honnayakanahalli Marichannegowda, Saini Setua, Meera Bose, Eric Sanders-Buell, David King, Michelle Zemil, Lindsay Wieczorek, Felisa Diaz-Mendez, Nicolas Chomont, Rasmi Thomas, Leilani Francisco, Leigh Anne Eller, Victoria R Polonis, Sodsai Tovanabutra, Alonso Heredia, Yutaka Tagaya, Nelson L Michael, Merlin L Robb, Hongshuo Song","doi":"10.1016/j.ebiom.2024.105410","DOIUrl":"10.1016/j.ebiom.2024.105410","url":null,"abstract":"<p><strong>Background: </strong>Nearly all transmitted/founder (T/F) HIV-1 are CCR5 (R5)-tropic. While previous evidence suggested that CXCR4 (X4)-tropic HIV-1 are transmissible, virus detection and characterization were not at the earliest stages of acute infection.</p><p><strong>Methods: </strong>We identified an X4-tropic T/F HIV-1 in a participant (40700) in the RV217 acute infection cohort. Coreceptor usage was determined in TZM-bl cell line, NP-2 cell lines, and primary CD4⁺ T cells using pseudovirus and infectious molecular clones. CD4 subset dynamics were analyzed using flow cytometry. Viral load in each CD4 subset was quantified using cell-associated HIV RNA assay and total and integrated HIV DNA assay.</p><p><strong>Findings: </strong>Participant 40700 was infected by an X4 tropic HIV-1 without CCR5 using ability. This participant experienced significantly faster CD4 depletion compared to R5 virus infected individuals in the same cohort. Naïve and central memory (CM) CD4 subsets declined faster than effector memory (EM) and transitional memory (TM) subsets. All CD4 subsets, including the naïve, were productively infected. Increased CD4⁺ T cell activation was observed over time. This X4-tropic T/F virus is resistant to broadly neutralizing antibodies (bNAbs) targeting V1/V2 and V3 regions, while most of the R5 T/F viruses in the same cohort are sensitive to the same panel of bNAbs.</p><p><strong>Interpretation: </strong>X4-tropic HIV-1 is transmissible through mucosal route in people with wild-type CCR5 genotype. The CD4 subset tropism of HIV-1 may be an important determinant for HIV-1 transmissibility and virulence.</p><p><strong>Funding: </strong>Institute of Human Virology, National Institutes of Health, Henry M. Jackson Foundation for the Advancement of Military Medicine.</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":null,"pages":null},"PeriodicalIF":9.7,"publicationDate":"2024-10-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11533037/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142460658","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":"Plasma proteomic signatures of liver steatosis and fibrosis in people living with HIV: a cross-sectional study.","authors":"Louise E van Eekeren, Quirijn de Mast, Elise M G Meeder, Adriana Navas, Albert L Groenendijk, Marc J T Blaauw, Wilhelm A J W Vos, Nadira Vadaq, Jéssica C Dos Santos, Joost Rutten, Niels P Riksen, Jan van Lunzen, Gert Weijers, Mihai G Netea, André J A M van der Ven, Eric T T L Tjwa, Leo A B Joosten","doi":"10.1016/j.ebiom.2024.105407","DOIUrl":"10.1016/j.ebiom.2024.105407","url":null,"abstract":"<p><strong>Background: </strong>Insights into the mechanisms driving metabolic dysfunction-associated steatotic liver disease (MASLD) in people living with HIV (PLHIV) remain limited. Plasma proteomics holds promise for biomarker discovery and the elucidation of biological mechanisms.</p><p><strong>Methods: </strong>We performed cross-sectional analyses on data from 1036 virally suppressed PLHIV using antiretroviral treatment (ART) from the Dutch multi-centre 2000HIV cohort. Participants underwent transient elastography to assess liver steatosis (controlled attenuation parameter (CAP) ≥263 dB/m) and -fibrosis (liver stiffness measurement (LSM) ≥7.0 kPa). Plasma protein concentrations (n = 2367) (Olink® Explore Panel) were compared between PLHIV with vs. without liver steatosis and PLHIV with vs. without fibrosis. Enriched pathways (using GO, KEGG and Reactome libraries) and correlations with clinical characteristics were assessed, and analyses were stratified by BMI category. In addition, concentrations of 242 proteins were compared between individuals (\"controls\") with and without liver steatosis (ratio of methylene:methylene and water >5.6% on magnetic resonance spectroscopy) from a separate cohort (300-OB), all having a BMI >26 kg/m².</p><p><strong>Findings: </strong>Steatosis and fibrosis were associated with 67/2367 (2.2%) and 17/2367 (0.7%) differentially expressed proteins (DEP), respectively, enriched in mostly metabolic pathways. Immunoglobulin superfamily member 9 (IGSF9) was amongst the top DEP associated with both steatosis and fibrosis. Stratifying by BMI revealed 8/2367 DEP associated with steatosis in lean- and 12/2367 DEP in overweight/obese individuals, with two shared DEP (IGSF9 and GHR). Conversely, protein signatures of overweight/obese PLHIV (32/242 DEP) and overweight/obese HIV-uninfected individuals (32/242 DEP) exhibited substantial overlap with 16 shared DEP. Notably, DEP correlated with HIV characteristics in lean individuals but not in overweight/obese PLHIV.</p><p><strong>Interpretation: </strong>Lean and overweight/obese PLHIV exhibit distinct proteomic signatures associated with liver steatosis, with the former being more strongly correlated with HIV-specific factors and ART. In addition, we identified a protein, IGSF9, strongly related to liver fibrosis and steatosis across BMI categories.</p><p><strong>Funding: </strong>The 2000HIV study is funded by ViiV Healthcare.</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":null,"pages":null},"PeriodicalIF":9.7,"publicationDate":"2024-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11513669/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142460718","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":"Single-chain A35R-M1R-B6R trivalent mRNA vaccines protect mice against both mpox virus and vaccinia virus.","authors":"Tianxiang Kong, Pei Du, Renyi Ma, Han Wang, Xuehui Ma, Jian Lu, Zhengrong Gao, Hai Qi, Ruiqi Li, Hao Zhang, Fei Xia, Yuanlang Liu, Ruyu Wang, Kai Duan, Zejun Wang, Qihui Wang, George F Gao","doi":"10.1016/j.ebiom.2024.105392","DOIUrl":"10.1016/j.ebiom.2024.105392","url":null,"abstract":"<p><strong>Background: </strong>Mpox has spread to many countries around the world. While the existing live attenuated mpox vaccines are effective, advances in 21st century technologies now enable the development of vaccines with more specific antigens, clearer mechanisms, and more controllable side effects.</p><p><strong>Methods: </strong>We systematically evaluated the immunogenicity and protective efficacy of the A35R, M1R and B6R antigens of the mpox virus (MPXV). With these findings, we designed three single-chain trivalent mRNA vaccines (AMAB-wt, AMAB-C140S and AMB-C140S) by integrating the soluble regions of these antigens into single mRNA-encoded polypeptides based on their protein structures. Then, the immunogenicity and protective efficacy of these single-chain mRNA vaccines were evaluated in mice models against both VACV and MPXV.</p><p><strong>Findings: </strong>The three single-chain vaccines elicited neutralising antibodies that effectively neutralised both VACV and MPXV. The single-chain vaccines or cocktail vaccine containing mRNAs encoding soluble antigen (sA35R + sM1R + sB6R) exhibited 100% or 80% protection against a lethal dose of VACV challenge, while the cocktail of full-length antigens (A35 + M1 + B6) and the live attenuated vaccine, VACV Tian Tan (VACV-VTT), completely failed to protect mice. Moreover, the single-chain vaccines significantly reduced viral load in the lungs and ovaries of MPXV-challenged mice.</p><p><strong>Interpretation: </strong>Compared with the cocktail vaccines, our single-chain designs demonstrated similar or superior immunogenicity and protective efficacy. Importantly, the simplicity of the single-chain vaccines enhances both the controllability and accessibility of mpox vaccines. We believe these single-chain vaccines qualify as the next-generation mpox vaccines.</p><p><strong>Funding: </strong>National Natural Science Foundation of China and Youth Innovation Promotion Association of the CAS.</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":null,"pages":null},"PeriodicalIF":9.7,"publicationDate":"2024-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11513793/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142460720","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":"Integrated single-cell transcriptomic analyses identify a novel lineage plasticity-related cancer cell type involved in prostate cancer progression.","authors":"Faming Zhao, Tingting Zhang, Jinlan Wei, Liang Chen, Zaoqu Liu, Yang Jin, Mingsheng Liu, Hongqing Zhou, Yanxia Hu, Xia Sheng","doi":"10.1016/j.ebiom.2024.105398","DOIUrl":"10.1016/j.ebiom.2024.105398","url":null,"abstract":"<p><strong>Background: </strong>Cancer cell plasticity is the ability of neoplastic cells to alter their identity and acquire new biological properties under microenvironmental pressures. In prostate cancer (PCa), lineage plasticity often results in therapy resistance and trans-differentiation to neuroendocrine (NE) lineage. However, identifying the cancer cells harboring lineage plasticity-related status remains challenging.</p><p><strong>Methods: </strong>Based on 13 multi-center human PCa bulk transcriptomic cohorts (samples = 3314) and 9 bulk transcriptomic datasets derived from PCa experimental models, we established an integrated lineage plasticity-related gene signature, termed LPSig. Leveraging this gene signature, AUCell enrichment analysis was applied to identify the cell population with high lineage plasticity from a comprehensive single-cell RNA-sequencing (scRNA-seq) meta-atlas assembled by us, which consisted of 10 public human PCa scRNA-seq datasets (samples = 93, cells = 222,529). Moreover, additional scRNA-seq dataset of human PCa, multiplex immunohistochemistry staining for human PCa tissues, in vitro and in vivo functional experiments, as well as qPCR and Western blot analyses were employed to validate our findings.</p><p><strong>Findings: </strong>We found that LPSig could finely capture the dynamics of tumor lineage plasticity throughout the progression of PCa, accurately estimating the status of lineage plasticity. Based on LPSig, we identified a previously undefined minority population of lineage plasticity-related PCa cells (LPCs) from the human PCa scRNA-seq meta-atlas assembled by this study. Furthermore, in-depth dissection revealed pivotal roles of LPCs in trans-differentiation, tumor recurrence, and poor patient survival during PCa progression. Furthermore, we identified HMMR as a representative cell surface marker for LPCs, which was validated using additional scRNA-seq datasets and multiplexed immunohistochemistry. Moreover, HMMR was transcriptionally inhibited by androgen receptor (AR), and was required for the aggressive adenocarcinoma features and NE phenotype.</p><p><strong>Interpretation: </strong>Our study uncovers a novel population of lineage plasticity-related cells with low AR activity, stemness-like traits, and elevated HMMR expression, that may facilitate poor prognosis in PCa.</p><p><strong>Funding: </strong>This work was supported by National Key R&D Program of China (2022YFA0807000), National Natural Science Foundation of China (82160584), Advanced Prostate Cancer Diagnosis and Treatment Technology Innovation Team of Kunming Medical University (CXTD202216), and Reserve Talents of Young and Middle-aged Academic Leaders in Yunnan Province (202105AC160013).</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":null,"pages":null},"PeriodicalIF":9.7,"publicationDate":"2024-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11530610/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142460704","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":"The impact of temperature on non-typhoidal Salmonella and Campylobacter infections: an updated systematic review and meta-analysis of epidemiological evidence.","authors":"Yohannes Tefera Damtew, Michael Tong, Blesson Mathew Varghese, Olga Anikeeva, Alana Hansen, Keith Dear, Tim Driscoll, Ying Zhang, Tony Capon, Peng Bi","doi":"10.1016/j.ebiom.2024.105393","DOIUrl":"10.1016/j.ebiom.2024.105393","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Background: &lt;/strong&gt;As temperatures rise, the transmission and incidence of enteric infections such as those caused by Salmonella and Campylobacter increase. This study aimed to review and synthesise the available evidence on the effects of exposure to ambient temperatures on non-typhoidal Salmonella and Campylobacter infections.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;A systematic search was conducted for peer-reviewed epidemiological studies published between January 1990 and March 2024, in PubMed, Scopus, Embase, and Web of Science databases. Original observational studies using ecological time-series, case-crossover or case-series study designs reporting the association between ambient temperature and non-typhoidal Salmonella and Campylobacter infections in the general population were included. A random-effects meta-analysis was performed to pool the relative risks (RRs) per 1 °C temperature increase, and further meta regression, and subgroup analyses by climate zone, temperature metrics, temporal resolution, lag period, and continent were conducted. The Navigation Guide systematic review methodology framework was used to assess the quality and strength of evidence. The study protocol was registered with the International Prospective Register of Systematic Reviews (PROSPERO).&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Findings: &lt;/strong&gt;Out of 3472 results, 44 studies were included in this systematic review encompassing over one million cases each of Salmonella and Campylobacter infections. Geographically, the 44 studies covered 27 countries across five continents and most of the studies were from high income countries. The meta-analysis incorporated 23 Salmonella studies (65 effect estimates) and 15 Campylobacter studies (24 effect estimates). For each 1 °C rise in temperature, the risk of non-typhoidal Salmonella and Campylobacter infections increased by 5% (RR: 1.05, 95% CI: 1.04-1.06), and 5% (RR: 1.05, 95% CI: 1.04-1.07%), respectively, with varying risks across different climate zones. The overall evidence was evaluated as being of \"high\" quality, and the strength of the evidence was determined to be \"sufficient\" for both infections.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Interpretation: &lt;/strong&gt;These findings emphasise the relationship between temperature and the incidence of Salmonella and Campylobacter infections. It is crucial to exercise caution when generalising these findings, given the limited number of studies conducted in low and middle-income countries. Nevertheless, the results demonstrate the importance of implementing focused interventions and adaptive measures, such as the establishment of localised early warning systems and preventive strategies that account for climatic fluctuations. Furthermore, our research emphasises the ongoing need for surveillance and research efforts to monitor and understand the changing dynamics of temperature-related enteric infections in the context of climate change.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Funding: &lt;/strong&gt;Australian Research Council Discovery Pro","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":null,"pages":null},"PeriodicalIF":9.7,"publicationDate":"2024-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11530612/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142460657","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":"Intermittent preventive treatment for malaria in pregnancy and infant growth: a mediation analysis of a randomised trial.","authors":"Yanwei Tong, Kalani Ratnasiri, Suhi Hanif, Anna T Nguyen, Michelle E Roh, Grant Dorsey, Abel Kakuru, Prasanna Jagannathan, Jade Benjamin-Chung","doi":"10.1016/j.ebiom.2024.105397","DOIUrl":"10.1016/j.ebiom.2024.105397","url":null,"abstract":"<p><strong>Background: </strong>Intermittent preventive treatment for malaria in pregnancy (IPTp) can improve birth outcomes, but whether it confers benefits to postnatal growth is unclear. We investigated the effect of IPTp on infant growth in Uganda and its pathways of effects using causal mediation analyses.</p><p><strong>Methods: </strong>We analysed data from 633 infants born to mothers enrolled in a randomised trial of monthly IPTp with dihydroartemisinin-piperaquine (DP) vs. sulfadoxine-pyrimethamine (SP) (NCT02793622). Weight and length were measured from 0 to 12 months of age. Using generalised linear models, we estimated effects of DP vs. SP on gravidity-stratified mean length-for-age (LAZ) and weight-for-length Z-scores (WLZ). We investigated mediation by placental malaria, gestational weight change, maternal anaemia, maternal inflammation-related proteins, preterm birth, birth length, and birth weight. Mediation models adjusted for infant sex, gravidity, gestational age at enrolment, maternal age, maternal parasitaemia at enrolment, education, and wealth.</p><p><strong>Findings: </strong>SP increased mean LAZ by 0.18-0.28 Z from birth through age 4 months compared to DP, while DP increased mean WLZ by 0.11-0.28 Z from 2 to 8 months compared to SP among infants of multigravidae; at these ages, confidence intervals for mean differences excluded 0. We did not observe differences among primigravida. Mediators of SP included birth weight, birth length, maternal stem cell factor, and DNER. Mediators of DP included placental malaria and birth length, maternal IL-18, CDCP1, and CD6 at delivery.</p><p><strong>Interpretation: </strong>In high malaria transmission settings, this exploratory study suggests different IPTp regimens may influence infant growth among multigravidae, potentially through distinct pathways, in the exclusive breastfeeding period, when few other interventions are available.</p><p><strong>Funding: </strong>Stanford Center for Innovation in Global Health, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bill & Melinda Gates Foundation.</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":null,"pages":null},"PeriodicalIF":9.7,"publicationDate":"2024-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11530852/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142460714","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":"Integration of circadian rhythms and immunotherapy for enhanced precision in brain cancer treatment.","authors":"Matthias Quist, Maas van Os, Linda W van Laake, Niels Bovenschen, Sandra Crnko","doi":"10.1016/j.ebiom.2024.105395","DOIUrl":"10.1016/j.ebiom.2024.105395","url":null,"abstract":"<p><p>Circadian rhythms significantly impact (patho)physiological processes, with disruptions linked to neurodegenerative diseases and heightened cancer vulnerability. While immunotherapy has shown promise in treating various cancers, its efficacy in brain malignancies remains limited. This review explores the nexus of circadian rhythms and immunotherapy in brain cancer treatment, emphasising precision through alignment with the body's internal clock. We evaluate circadian regulation of immune responses, including cell localisation and functional phenotype, and discuss how circadian dysregulation affects anti-cancer immunity. Additionally, we analyse and assess the effectiveness of current immunotherapeutic approaches for brain cancer including immune checkpoint blockades, adoptive cellular therapies, and other novel strategies. Future directions, such as chronotherapy and personalised treatment schedules, are proposed to optimise immunotherapy precision against brain cancers. Overall, this review provides an understanding of the often-overlooked role of circadian rhythms in brain cancer and suggests avenues for improving immunotherapeutic outcomes.</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":null,"pages":null},"PeriodicalIF":9.7,"publicationDate":"2024-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11530607/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142460713","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":"Patterns of the within-host evolution of human norovirus in immunocompromised individuals and implications for treatment.","authors":"Ray W Izquierdo-Lara, Nele Villabruna, Dennis A Hesselink, Claudia M E Schapendonk, Sol Ribó Pons, David Nieuwenhuijse, Jenny I J Meier, Ian Goodfellow, Virgil A S H Dalm, Pieter L A Fraaij, Jeroen J A van Kampen, Marion P G Koopmans, Miranda de Graaf","doi":"10.1016/j.ebiom.2024.105391","DOIUrl":"https://doi.org/10.1016/j.ebiom.2024.105391","url":null,"abstract":"<p><strong>Background: </strong>Currently, there is no licensed treatment for chronic norovirus infections, but the use of intra-duodenally-delivered immunoglobulins is promising; nevertheless, varying results have limited their wide use. Little is known about the relationship between norovirus genetic diversity and treatment efficacy.</p><p><strong>Methods: </strong>We analyzed the norovirus within-host diversity and evolution in a cohort of 20 immunocompromised individuals using next-generation sequencing (NGS) and clone-based sequencing of the capsid (VP1) gene. Representative VP1s were expressed and their glycan receptor binding affinity and antigenicity were evaluated.</p><p><strong>Findings: </strong>The P2 domain, within the VP1, accumulated up to 30-fold more non-synonymous mutations than other genomic regions. Intra-host virus populations in these patients tended to evolve into divergent lineages that were often antigenically distinct. Several of these viruses were widely resistant to binding-blocking antibodies in immunoglobulin preparations. Notably, for one patient, a single amino-acid substitution in the P2 domain resulted in an immune-escape phenotype, and it was likely the main contributor to treatment failure. Furthermore, we found evidence for transmission of late-stage viruses between two immunocompromised individuals.</p><p><strong>Interpretation: </strong>The findings demonstrated that within-host noroviruses in chronic infections tend to evolve into antigenically distinct subpopulations. This antigenic evolution was likely caused by the remaining low immunity levels exerted by immunocompromised individuals, possibly undermining antiviral treatment. Our observations provide insights into norovirus (within-host) evolution and treatment.</p><p><strong>Funding: </strong>Erasmus MC grant mRACE, the European Union's Horizon 2020 research and innovation program under grant agreement No. 874735 (VEO), and the NWO STEVIN award (Koopmans).</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":null,"pages":null},"PeriodicalIF":9.7,"publicationDate":"2024-10-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142460716","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}