Pub Date : 2024-08-26DOI: 10.1016/j.ebiom.2024.105309
Wenjuan Liu, Yawen Sun, Yanfei Huo, Long Zhang, Nasha Zhang, Ming Yang
LC is one of the most common malignant tumours that often presents with no distinct symptoms in the early stages, leading to late diagnoses when patients are at an advanced stage and no longer suitable for surgical treatment. Although adjuvant treatments are available, patients frequently develop tolerance to these treatments over time, resulting in poor prognoses for patients with advanced LC. Recently, circular RNAs (circRNAs), a type of non-coding RNA, have gained significant attention in LC research. Owing to their unique circular structure, circRNAs are highly stable within cells. This review systematically summarises the expression, characteristics, biological functions, and molecular regulatory mechanisms of circRNAs involved in therapy resistance as well as the potential applications in early diagnosis and gene targeting therapy in LC.
{"title":"Circular RNAs in lung cancer: implications for preventing therapeutic resistance.","authors":"Wenjuan Liu, Yawen Sun, Yanfei Huo, Long Zhang, Nasha Zhang, Ming Yang","doi":"10.1016/j.ebiom.2024.105309","DOIUrl":"https://doi.org/10.1016/j.ebiom.2024.105309","url":null,"abstract":"<p><p>LC is one of the most common malignant tumours that often presents with no distinct symptoms in the early stages, leading to late diagnoses when patients are at an advanced stage and no longer suitable for surgical treatment. Although adjuvant treatments are available, patients frequently develop tolerance to these treatments over time, resulting in poor prognoses for patients with advanced LC. Recently, circular RNAs (circRNAs), a type of non-coding RNA, have gained significant attention in LC research. Owing to their unique circular structure, circRNAs are highly stable within cells. This review systematically summarises the expression, characteristics, biological functions, and molecular regulatory mechanisms of circRNAs involved in therapy resistance as well as the potential applications in early diagnosis and gene targeting therapy in LC.</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":null,"pages":null},"PeriodicalIF":9.7,"publicationDate":"2024-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142079634","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}
Pub Date : 2024-08-24DOI: 10.1016/j.ebiom.2024.105304
Jaime D Rhodes, Aishwarya Devaraj, Frank Robledo-Avila, Sabarathnam Balu, Lauren Mashburn-Warren, John R Buzzo, Santiago Partida-Sanchez, Lauren O Bakaletz, Steven D Goodman
Background: Bacterial biofilm communities are embedded in a protective extracellular matrix comprised of various components, with its' integrity largely owed to a 3-dimensional lattice of extracellular DNA (eDNA) interconnected by Holliday Junction (HJ)-like structures and stabilised by the ubiquitous eubacterial DNABII family of DNA-binding architectural proteins. We recently showed that the host innate immune effector High Mobility Group Box 1 (HMGB1) protein possesses extracellular anti-biofilm activity by destabilising these HJ-like structures, resulting in release of biofilm-resident bacteria into a vulnerable state. Herein, we showed that HMGB1's anti-biofilm activity was completely contained within a contiguous 97 amino acid region that retained DNA-binding activity, called 'mB Box-97'.
Methods: We engineered a synthetic version of this 97-mer and introduced a single amino acid change which lacked any post-translational modifications, and tested its activity independently and in combination with a humanised monoclonal antibody that disrupts biofilms by the distinct mechanism of DNABII protein sequestration.
Findings: mB Box-97 disrupted and prevented biofilms, including those formed by the ESKAPEE pathogens, and importantly reduced measurable proinflammatory activity normally associated with HMGB1 in a murine lung infection model.
Interpretation: Herein, we discuss the value of targeting the ubiquitous eDNA-dependent matrix of biofilms via mB Box-97 used singly or in a dual host-augmenting/pathogen-targeted cocktail to resolve bacterial biofilm infections.
Funding: This work was supported by NIH/NIDCD R01DC011818 to L.O.B. and S.D.G. and NIH/NIAID R01AI155501 to S.D.G.
{"title":"Noninflammatory 97-amino acid High Mobility Group Box 1 derived polypeptide disrupts and prevents diverse biofilms.","authors":"Jaime D Rhodes, Aishwarya Devaraj, Frank Robledo-Avila, Sabarathnam Balu, Lauren Mashburn-Warren, John R Buzzo, Santiago Partida-Sanchez, Lauren O Bakaletz, Steven D Goodman","doi":"10.1016/j.ebiom.2024.105304","DOIUrl":"https://doi.org/10.1016/j.ebiom.2024.105304","url":null,"abstract":"<p><strong>Background: </strong>Bacterial biofilm communities are embedded in a protective extracellular matrix comprised of various components, with its' integrity largely owed to a 3-dimensional lattice of extracellular DNA (eDNA) interconnected by Holliday Junction (HJ)-like structures and stabilised by the ubiquitous eubacterial DNABII family of DNA-binding architectural proteins. We recently showed that the host innate immune effector High Mobility Group Box 1 (HMGB1) protein possesses extracellular anti-biofilm activity by destabilising these HJ-like structures, resulting in release of biofilm-resident bacteria into a vulnerable state. Herein, we showed that HMGB1's anti-biofilm activity was completely contained within a contiguous 97 amino acid region that retained DNA-binding activity, called 'mB Box-97'.</p><p><strong>Methods: </strong>We engineered a synthetic version of this 97-mer and introduced a single amino acid change which lacked any post-translational modifications, and tested its activity independently and in combination with a humanised monoclonal antibody that disrupts biofilms by the distinct mechanism of DNABII protein sequestration.</p><p><strong>Findings: </strong>mB Box-97 disrupted and prevented biofilms, including those formed by the ESKAPEE pathogens, and importantly reduced measurable proinflammatory activity normally associated with HMGB1 in a murine lung infection model.</p><p><strong>Interpretation: </strong>Herein, we discuss the value of targeting the ubiquitous eDNA-dependent matrix of biofilms via mB Box-97 used singly or in a dual host-augmenting/pathogen-targeted cocktail to resolve bacterial biofilm infections.</p><p><strong>Funding: </strong>This work was supported by NIH/NIDCD R01DC011818 to L.O.B. and S.D.G. and NIH/NIAID R01AI155501 to S.D.G.</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":null,"pages":null},"PeriodicalIF":9.7,"publicationDate":"2024-08-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142055240","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}
Pub Date : 2024-08-23DOI: 10.1016/j.ebiom.2024.105288
Harshraj Leuva, Mengxi Zhou, Nader Jamaleddine, Mina Meseha, Izak Faiena, Yeun-Hee Anna Park, Glen McWilliams, Carol Luhrs, Kara N Maxwell, Daniel Von Hoff, Susan E Bates, Tito Fojo
Background: We aimed to assess real-world efficacy of the PARP inhibitor, olaparib, in US Veterans with metastatic prostate cancer (mPC) by leveraging the national data repository and evaluate a novel approach to assess treatment efficacy in tumors considered rare or harboring rare mutations.
Methods: Included Veterans had 1) mPC with somatic or germline alterations/mutations in genes involved in homologous recombination repair (HRR), 2) received olaparib monotherapy as well as a novel hormonal therapy/androgen receptor pathway inhibitors (NHT/ARPI), and/or chemotherapy, and 3) estimable rates of tumor growth (g-rate) using PSA values obtained while receiving treatment. Previous work has shown an excellent inverse correlation of g-rate with survival. Using g-rate, we determined tumor doubling time (DT) and DT ratios (DT on olaparib/DT on prior medication). We postulated that a DT ratio≥ 1 was associated with benefit.
Findings: We identified 139 Veterans, including 42 Black males with tumors harboring mutations/alterations in HRR genes who received olaparib: BRCA2 (50), ATM (32), BRCA1 (10), other mutations (47). 62/139 (45%) of all and 21/42 (50%) of Black Veterans had DT ratios ≥1, including 31, 10, 2, and 19 with BRCA2, ATM, BRCA1, and other mutations, respectively (p = 0.006). Median survival with DT ratios ≥1 was superior, being 24.5 vs. 11.4 months for DT ratio <1 (p = 0.01, HR 0.50, 95% CI 0.29-0.85). Benefit from olaparib, defined as DT ratio ≥1, was not observed for germline status, starting PSA value, number of prior therapies, or immediate prior therapy. Compared to matched cohorts, tumors in the olaparib cohort had shorter DTs with enzalutamide in first line (367 vs. 884 days; p = 0.0043).
Interpretation: Using equations indifferent to timing of assessments ideal for real-world efficacy analyses, we showed DT ratio ≥1 representing slower tumor growth on olaparib relative to the prior therapy correlates with improved survival. Olaparib efficacy in Veterans with mPC harboring mutations/alterations in HRR genes emulates clinical trial results. Black men had comparable results. Compared to matched cohorts, in first line, enzalutamide was less efficacious in tumors harboring mutations/alterations in HRR genes.
Funding: American Society of Clinical Oncology Conquer Cancer Foundation (ASCO CCF), the Blavatnik Family Foundation and the Prostate Cancer Foundation (PCF).
{"title":"Assessing olaparib efficacy in U.S. Veterans with metastatic prostate cancer utilizing a time-indifferent g-rate method ideal for real-world analyses.","authors":"Harshraj Leuva, Mengxi Zhou, Nader Jamaleddine, Mina Meseha, Izak Faiena, Yeun-Hee Anna Park, Glen McWilliams, Carol Luhrs, Kara N Maxwell, Daniel Von Hoff, Susan E Bates, Tito Fojo","doi":"10.1016/j.ebiom.2024.105288","DOIUrl":"https://doi.org/10.1016/j.ebiom.2024.105288","url":null,"abstract":"<p><strong>Background: </strong>We aimed to assess real-world efficacy of the PARP inhibitor, olaparib, in US Veterans with metastatic prostate cancer (mPC) by leveraging the national data repository and evaluate a novel approach to assess treatment efficacy in tumors considered rare or harboring rare mutations.</p><p><strong>Methods: </strong>Included Veterans had 1) mPC with somatic or germline alterations/mutations in genes involved in homologous recombination repair (HRR), 2) received olaparib monotherapy as well as a novel hormonal therapy/androgen receptor pathway inhibitors (NHT/ARPI), and/or chemotherapy, and 3) estimable rates of tumor growth (g-rate) using PSA values obtained while receiving treatment. Previous work has shown an excellent inverse correlation of g-rate with survival. Using g-rate, we determined tumor doubling time (DT) and DT ratios (DT on olaparib/DT on prior medication). We postulated that a DT ratio≥ 1 was associated with benefit.</p><p><strong>Findings: </strong>We identified 139 Veterans, including 42 Black males with tumors harboring mutations/alterations in HRR genes who received olaparib: BRCA2 (50), ATM (32), BRCA1 (10), other mutations (47). 62/139 (45%) of all and 21/42 (50%) of Black Veterans had DT ratios ≥1, including 31, 10, 2, and 19 with BRCA2, ATM, BRCA1, and other mutations, respectively (p = 0.006). Median survival with DT ratios ≥1 was superior, being 24.5 vs. 11.4 months for DT ratio <1 (p = 0.01, HR 0.50, 95% CI 0.29-0.85). Benefit from olaparib, defined as DT ratio ≥1, was not observed for germline status, starting PSA value, number of prior therapies, or immediate prior therapy. Compared to matched cohorts, tumors in the olaparib cohort had shorter DTs with enzalutamide in first line (367 vs. 884 days; p = 0.0043).</p><p><strong>Interpretation: </strong>Using equations indifferent to timing of assessments ideal for real-world efficacy analyses, we showed DT ratio ≥1 representing slower tumor growth on olaparib relative to the prior therapy correlates with improved survival. Olaparib efficacy in Veterans with mPC harboring mutations/alterations in HRR genes emulates clinical trial results. Black men had comparable results. Compared to matched cohorts, in first line, enzalutamide was less efficacious in tumors harboring mutations/alterations in HRR genes.</p><p><strong>Funding: </strong>American Society of Clinical Oncology Conquer Cancer Foundation (ASCO CCF), the Blavatnik Family Foundation and the Prostate Cancer Foundation (PCF).</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":null,"pages":null},"PeriodicalIF":9.7,"publicationDate":"2024-08-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142046462","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}
Pub Date : 2024-08-23DOI: 10.1016/j.ebiom.2024.105305
Yue Xu, Chunfeng He, Jiayao Fan, Yuan Zhou, Chunxiao Cheng, Ran Meng, Ya Cui, Wei Li, Eric R Gamazon, Dan Zhou
Background: Tissue-specific analysis of the transcriptome is critical to elucidating the molecular basis of complex traits, but central tissues are often not accessible. We propose a methodology, Multi-mOdal-based framework to bridge the Transcriptome between PEripheral and Central tissues (MOTPEC).
Methods: Multi-modal regulatory elements in peripheral blood are incorporated as features for gene expression prediction in 48 central tissues. To demonstrate the utility, we apply it to the identification of BMI-associated genes and compare the tissue-specific results with those derived directly from surrogate blood.
Findings: MOTPEC models demonstrate superior performance compared with both baseline models in blood and existing models across the 48 central tissues. We identify a set of BMI-associated genes using the central tissue MOTPEC-predicted transcriptome data. The MOTPEC-based differential gene expression (DGE) analysis of BMI in the central tissues (including brain caudate basal ganglia and visceral omentum adipose tissue) identifies 378 genes overlapping the results from a TWAS of BMI, while only 162 overlapping genes are identified using gene expression in blood. Cellular perturbation analysis further supports the utility of MOTPEC for identifying trait-associated gene sets and narrowing the effect size divergence between peripheral blood and central tissues.
Interpretation: The MOTPEC framework improves the gene expression prediction accuracy for central tissues and enhances the identification of tissue-specific trait-associated genes.
Funding: This research is supported by the National Natural Science Foundation of China 82204118 (D.Z.), the seed funding of the Key Laboratory of Intelligent Preventive Medicine of Zhejiang Province (2020E10004), the National Institutes of Health (NIH) Genomic Innovator Award R35HG010718 (E.R.G.), NIH/NHGRI R01HG011138 (E.R.G.), NIH/NIA R56AG068026 (E.R.G.), NIH Office of the Director U24OD035523 (E.R.G.), and NIH/NIGMS R01GM140287 (E.R.G.).
{"title":"A multi-modal framework improves prediction of tissue-specific gene expression from a surrogate tissue.","authors":"Yue Xu, Chunfeng He, Jiayao Fan, Yuan Zhou, Chunxiao Cheng, Ran Meng, Ya Cui, Wei Li, Eric R Gamazon, Dan Zhou","doi":"10.1016/j.ebiom.2024.105305","DOIUrl":"https://doi.org/10.1016/j.ebiom.2024.105305","url":null,"abstract":"<p><strong>Background: </strong>Tissue-specific analysis of the transcriptome is critical to elucidating the molecular basis of complex traits, but central tissues are often not accessible. We propose a methodology, Multi-mOdal-based framework to bridge the Transcriptome between PEripheral and Central tissues (MOTPEC).</p><p><strong>Methods: </strong>Multi-modal regulatory elements in peripheral blood are incorporated as features for gene expression prediction in 48 central tissues. To demonstrate the utility, we apply it to the identification of BMI-associated genes and compare the tissue-specific results with those derived directly from surrogate blood.</p><p><strong>Findings: </strong>MOTPEC models demonstrate superior performance compared with both baseline models in blood and existing models across the 48 central tissues. We identify a set of BMI-associated genes using the central tissue MOTPEC-predicted transcriptome data. The MOTPEC-based differential gene expression (DGE) analysis of BMI in the central tissues (including brain caudate basal ganglia and visceral omentum adipose tissue) identifies 378 genes overlapping the results from a TWAS of BMI, while only 162 overlapping genes are identified using gene expression in blood. Cellular perturbation analysis further supports the utility of MOTPEC for identifying trait-associated gene sets and narrowing the effect size divergence between peripheral blood and central tissues.</p><p><strong>Interpretation: </strong>The MOTPEC framework improves the gene expression prediction accuracy for central tissues and enhances the identification of tissue-specific trait-associated genes.</p><p><strong>Funding: </strong>This research is supported by the National Natural Science Foundation of China 82204118 (D.Z.), the seed funding of the Key Laboratory of Intelligent Preventive Medicine of Zhejiang Province (2020E10004), the National Institutes of Health (NIH) Genomic Innovator Award R35HG010718 (E.R.G.), NIH/NHGRI R01HG011138 (E.R.G.), NIH/NIA R56AG068026 (E.R.G.), NIH Office of the Director U24OD035523 (E.R.G.), and NIH/NIGMS R01GM140287 (E.R.G.).</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":null,"pages":null},"PeriodicalIF":9.7,"publicationDate":"2024-08-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142046496","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}
Pub Date : 2024-08-22DOI: 10.1016/j.ebiom.2024.105289
Valentina Mazzotta, Silvia Nozza, Simone Lanini, Davide Moschese, Alessandro Tavelli, Roberto Rossotti, Francesco Maria Fusco, Lorenzo Biasioli, Giulia Matusali, Angelo Roberto Raccagni, Davide Mileto, Chiara Maci, Giuseppe Lapadula, Antonio Di Biagio, Luca Pipitò, Enrica Tamburrini, Antonella d'Arminio Monforte, Antonella Castagna, Andrea Antinori
<p><strong>Background: </strong>Severe and prolonged mpox courses have been described during the 2022-2023 outbreak. Identifying predictors of severe evolution is crucial for improving management and therapeutic strategies. We explored the predictors of mpox severity and tested the association between mpox severity and viral load in biological fluids. We also analysed the predictors of disease duration and kinetics of inflammatory markers and described the viral presence and duration of shedding in biological fluids.</p><p><strong>Methods: </strong>This multicentre historical cohort study included adults diagnosed with laboratory-confirmed mpox diagnosis between May 2022 and September 2023 at 15 Italian centres. Patients were followed up from the day of diagnosis until clinical recovery. Biological fluids (blood, urine, saliva, and oropharyngeal and rectal swabs) were collected from each subgroup during the course of the disease and after healing. The primary outcomes were disease severity (presence of mucosal involvement, extended rash, or need for hospitalisation) and its association with the cycle threshold value (Ct-value, surrogate of viral load) in biological fluids, using standard linear and linear mixed-effect logistic regression models. Among the secondary outcomes, predictors of disease duration were assessed using a linear regression model.</p><p><strong>Findings: </strong>A total of 541 patients were enrolled, including four (0.74%) women, with a median age of 38 years (IQR 33-44). Among the 235 people living with HIV (PLWH) (43.44%), 22 (4.07%) had a CD4 count lower than 350 cells/μL. Severe mpox was reported in 215 patients (39.74%). No patient died. Multivariable analysis showed that, severe mpox was more likely among Caucasians (OR 1.82; 95% CI 1.14-2.90, p = 0.012) and patients who had an onset of fever (1.95; 1.27-2.99, p = 0.002), lymphadenopathy (2.30; 1.52-3.48, p < 0.001), sore throat (2.14; 1.27-3.59, p = 0.004), and peri-anal lesions (2.91; 1.93-4.37, p < 0.001). There was a significant difference (p = 0.003) between the median Ct-value in the upper respiratory tract for patients presenting with either mild (35.15; IQR 28.77-42.01) or severe infection (31.00; 25.00-42.01). The risk of developing severe disease decreased by approximately 5% per Ct increase (0.95; 0.91-0.98; p = 0.005). The disease lasted longer in the case of proctitis (+4.78 days; 1.95-7.61, p = 0.001), sore throat (+3.12; 0.05-6.20, p = 0.046), extended rash (+3.42; 0.55-6.28, p = 0.020), as well as in PLWH with a low CD4 count (+12.51; 6.79-18.22, p < 0.001).</p><p><strong>Interpretation: </strong>The identification of predictors of severe or prolonged disease and the direct association MPXV Ct-value in the upper respiratory tract and disease severity could be useful in establishing proper management and early treatment of new mpox cases.</p><p><strong>Funding: </strong>ICONA Foundation; Italian Ministry of Health "Ricerca Corrente Linea 2", INMI Lazzaro
{"title":"Clinical and laboratory predictors of mpox severity and duration: an Italian multicentre cohort study (mpox-Icona).","authors":"Valentina Mazzotta, Silvia Nozza, Simone Lanini, Davide Moschese, Alessandro Tavelli, Roberto Rossotti, Francesco Maria Fusco, Lorenzo Biasioli, Giulia Matusali, Angelo Roberto Raccagni, Davide Mileto, Chiara Maci, Giuseppe Lapadula, Antonio Di Biagio, Luca Pipitò, Enrica Tamburrini, Antonella d'Arminio Monforte, Antonella Castagna, Andrea Antinori","doi":"10.1016/j.ebiom.2024.105289","DOIUrl":"https://doi.org/10.1016/j.ebiom.2024.105289","url":null,"abstract":"<p><strong>Background: </strong>Severe and prolonged mpox courses have been described during the 2022-2023 outbreak. Identifying predictors of severe evolution is crucial for improving management and therapeutic strategies. We explored the predictors of mpox severity and tested the association between mpox severity and viral load in biological fluids. We also analysed the predictors of disease duration and kinetics of inflammatory markers and described the viral presence and duration of shedding in biological fluids.</p><p><strong>Methods: </strong>This multicentre historical cohort study included adults diagnosed with laboratory-confirmed mpox diagnosis between May 2022 and September 2023 at 15 Italian centres. Patients were followed up from the day of diagnosis until clinical recovery. Biological fluids (blood, urine, saliva, and oropharyngeal and rectal swabs) were collected from each subgroup during the course of the disease and after healing. The primary outcomes were disease severity (presence of mucosal involvement, extended rash, or need for hospitalisation) and its association with the cycle threshold value (Ct-value, surrogate of viral load) in biological fluids, using standard linear and linear mixed-effect logistic regression models. Among the secondary outcomes, predictors of disease duration were assessed using a linear regression model.</p><p><strong>Findings: </strong>A total of 541 patients were enrolled, including four (0.74%) women, with a median age of 38 years (IQR 33-44). Among the 235 people living with HIV (PLWH) (43.44%), 22 (4.07%) had a CD4 count lower than 350 cells/μL. Severe mpox was reported in 215 patients (39.74%). No patient died. Multivariable analysis showed that, severe mpox was more likely among Caucasians (OR 1.82; 95% CI 1.14-2.90, p = 0.012) and patients who had an onset of fever (1.95; 1.27-2.99, p = 0.002), lymphadenopathy (2.30; 1.52-3.48, p < 0.001), sore throat (2.14; 1.27-3.59, p = 0.004), and peri-anal lesions (2.91; 1.93-4.37, p < 0.001). There was a significant difference (p = 0.003) between the median Ct-value in the upper respiratory tract for patients presenting with either mild (35.15; IQR 28.77-42.01) or severe infection (31.00; 25.00-42.01). The risk of developing severe disease decreased by approximately 5% per Ct increase (0.95; 0.91-0.98; p = 0.005). The disease lasted longer in the case of proctitis (+4.78 days; 1.95-7.61, p = 0.001), sore throat (+3.12; 0.05-6.20, p = 0.046), extended rash (+3.42; 0.55-6.28, p = 0.020), as well as in PLWH with a low CD4 count (+12.51; 6.79-18.22, p < 0.001).</p><p><strong>Interpretation: </strong>The identification of predictors of severe or prolonged disease and the direct association MPXV Ct-value in the upper respiratory tract and disease severity could be useful in establishing proper management and early treatment of new mpox cases.</p><p><strong>Funding: </strong>ICONA Foundation; Italian Ministry of Health \"Ricerca Corrente Linea 2\", INMI Lazzaro","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":null,"pages":null},"PeriodicalIF":9.7,"publicationDate":"2024-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142046464","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}
Pub Date : 2024-08-22DOI: 10.1016/j.ebiom.2024.105301
Jieyu Liu, Yinan Bai, Yinggang Li, Xiaoling Li, Kui Luo
Increasing evidence indicates that immunotherapy is hindered by a hostile tumor microenvironment (TME) featured with deprivation of critical nutrients and pooling of immunosuppressive metabolites. Tumor cells and immunosuppressive cells outcompete immune effector cells for essential nutrients. Meanwhile, a wide range of tumor cell-derived toxic metabolites exerts negative impacts on anti-tumor immune response, diminishing the efficacy of immunotherapy. Nanomedicine with excellent targetability offers a novel approach to improving cancer immunotherapy via metabolically reprogramming the immunosuppressive TME. Herein, we review recent strategies of enhancing immunotherapeutic effects through rewiring tumor metabolism via nanomedicine. Attention is drawn on immunometabolic tactics for immune cells and stromal cells in the TME via nanomedicine. Additionally, we discuss future directions of developing metabolism-regulating nanomedicine for precise and efficacious cancer immunotherapy.
{"title":"Reprogramming the immunosuppressive tumor microenvironment through nanomedicine: an immunometabolism perspective.","authors":"Jieyu Liu, Yinan Bai, Yinggang Li, Xiaoling Li, Kui Luo","doi":"10.1016/j.ebiom.2024.105301","DOIUrl":"https://doi.org/10.1016/j.ebiom.2024.105301","url":null,"abstract":"<p><p>Increasing evidence indicates that immunotherapy is hindered by a hostile tumor microenvironment (TME) featured with deprivation of critical nutrients and pooling of immunosuppressive metabolites. Tumor cells and immunosuppressive cells outcompete immune effector cells for essential nutrients. Meanwhile, a wide range of tumor cell-derived toxic metabolites exerts negative impacts on anti-tumor immune response, diminishing the efficacy of immunotherapy. Nanomedicine with excellent targetability offers a novel approach to improving cancer immunotherapy via metabolically reprogramming the immunosuppressive TME. Herein, we review recent strategies of enhancing immunotherapeutic effects through rewiring tumor metabolism via nanomedicine. Attention is drawn on immunometabolic tactics for immune cells and stromal cells in the TME via nanomedicine. Additionally, we discuss future directions of developing metabolism-regulating nanomedicine for precise and efficacious cancer immunotherapy.</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":null,"pages":null},"PeriodicalIF":9.7,"publicationDate":"2024-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142046468","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}
Pub Date : 2024-08-22DOI: 10.1016/j.ebiom.2024.105294
Zuo-Lin Li, Xin-Yan Li, Yan Zhou, Bin Wang, Lin-Li Lv, Bi-Cheng Liu
Acute kidney injury (AKI) is a clinical syndrome characterized by a rapid and significant decrease in renal function that can arise from various etiologies, and is associated with high morbidity and mortality. The renal tubular epithelial cells (TECs) represent the central cell type affected by AKI, and their notable regenerative capacity is critical for the recovery of renal function in afflicted patients. The adaptive repair process initiated by surviving TECs following mild AKI facilitates full renal recovery. Conversely, when injury is severe or persistent, it allows the TECs to undergo pathological responses, abnormal adaptive repair and phenotypic transformation, which will lead to the development of renal fibrosis. Given the implications of TECs fate after injury in renal outcomes, a deeper understanding of these mechanisms is necessary to identify promising therapeutic targets and biomarkers of the repair process in the human kidney.
急性肾损伤(AKI)是一种临床综合征,其特点是肾功能迅速显著下降,可由各种病因引起,与高发病率和高死亡率相关。肾小管上皮细胞(TEC)是受 AKI 影响的核心细胞类型,其显著的再生能力对患者肾功能的恢复至关重要。轻度 AKI 后,存活的 TEC 启动的适应性修复过程有助于肾功能的完全恢复。相反,如果损伤严重或持续,则会使 TECs 发生病理反应、异常适应性修复和表型转化,从而导致肾脏纤维化的发展。鉴于损伤后 TECs 的命运对肾脏预后的影响,有必要深入了解这些机制,以确定有前景的治疗目标和人类肾脏修复过程的生物标志物。
{"title":"Renal tubular epithelial cells response to injury in acute kidney injury.","authors":"Zuo-Lin Li, Xin-Yan Li, Yan Zhou, Bin Wang, Lin-Li Lv, Bi-Cheng Liu","doi":"10.1016/j.ebiom.2024.105294","DOIUrl":"https://doi.org/10.1016/j.ebiom.2024.105294","url":null,"abstract":"<p><p>Acute kidney injury (AKI) is a clinical syndrome characterized by a rapid and significant decrease in renal function that can arise from various etiologies, and is associated with high morbidity and mortality. The renal tubular epithelial cells (TECs) represent the central cell type affected by AKI, and their notable regenerative capacity is critical for the recovery of renal function in afflicted patients. The adaptive repair process initiated by surviving TECs following mild AKI facilitates full renal recovery. Conversely, when injury is severe or persistent, it allows the TECs to undergo pathological responses, abnormal adaptive repair and phenotypic transformation, which will lead to the development of renal fibrosis. Given the implications of TECs fate after injury in renal outcomes, a deeper understanding of these mechanisms is necessary to identify promising therapeutic targets and biomarkers of the repair process in the human kidney.</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":null,"pages":null},"PeriodicalIF":9.7,"publicationDate":"2024-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142046467","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}
Pub Date : 2024-08-22DOI: 10.1016/j.ebiom.2024.105274
Alexis Yero, Jean-Philippe Goulet, Tao Shi, Cecilia T Costiniuk, Jean-Pierre Routy, Cecile Tremblay, Ralph-Sydney Mboumba Bouassa, Yulia Alexandrova, Amélie Pagliuzza, Nicolas Chomont, Petronela Ancuta, Mohammad-Ali Jenabian
Background: Despite successful antiretroviral therapy (ART), frequencies and immunological functions of memory CCR6+ Th17-polarised CD4+ T-cells are not fully restored in people with HIV (PWH). Moreover, long-lived Th17 cells contribute to HIV persistence under ART. However, the molecular mechanisms underlying these observations remain understudied.
Methods: mRNA-sequencing was performed using Illumina technology on freshly FACS-sorted memory CCR6+CD4+ T-cells from successfully ART-treated (ST), elite controllers (EC), and uninfected donors (HD). Gene expression validation was performed by RT-PCR, flow cytometry, and in vitro functional assays.
Findings: Decreased Th17 cell frequencies in STs and ECs versus HDs coincided with reduced Th17-lineage cytokine production in vitro. Accordingly, the RORγt/RORC2 repressor NR1D1 was upregulated, while the RORγt/RORC2 inducer Semaphorin 4D was decreased in memory CCR6+ T-cells of STs and ECs versus HDs. The presence of HIV-DNA in memory CCR6+ T-cells of ST and EC corresponded with the downregulation of HIV restriction factors (SERINC3, KLF3, and RNF125) and HIV inhibitors (tetraspanins), along with increased expression of the HIV-dependency factor MRE11, indicative of higher susceptibility/permissiveness to HIV-1 infection. Furthermore, markers of DNA damage/modification were elevated in memory CCR6+ T-cells of STs and ECs versus HDs, in line with their increased activation (CD38/HLA-DR), senescence/exhaustion phenotype (CTLA-4/PD-1/CD57) and their decreased expression of proliferation marker Ki-67.
Interpretation: These results reveal new molecular mechanisms of Th17 cell deficit in ST and EC PWH despite a successful control of HIV-1 replication. This knowledge points to potential therapeutic interventions to limit HIV-1 infection and restore frequencies, effector functions, and senescence/exhaustion in Th17 cells.
Funding: This study was funded by the Canadian Institutes of Health Research (CIHR, operating grant MOP 142294, and the Canadian HIV Cure Enterprise [CanCURE 2.0] Team Grant HB2 164064), and in part, by the Réseau SIDA et maladies infectieuses du Fonds de recherche du Québec-Santé (FRQ-S).
背景:尽管抗逆转录病毒疗法(ART)取得了成功,但在艾滋病毒感染者(PWH)中,记忆性 CCR6+ Th17 极化 CD4+ T 细胞的频率和免疫功能并未完全恢复。此外,在抗逆转录病毒疗法(ART)下,长效 Th17 细胞会导致 HIV 持续存在。方法:使用 Illumina 技术对来自成功接受抗逆转录病毒疗法(ST)、精英控制者(EC)和未感染供体(HD)的新鲜 FACS 分选记忆性 CCR6+CD4+ T 细胞进行 mRNA 测序。基因表达验证通过 RT-PCR、流式细胞术和体外功能测试进行:结果:STs和ECs中的Th17细胞频率相对于HDs有所降低,这与体外Th17系细胞因子产生的减少相吻合。相应地,RORγt/RORC2抑制因子NR1D1上调,而RORγt/RORC2诱导因子Semaphorin 4D在STs和ECs与HDs的记忆CCR6+ T细胞中减少。在 ST 和 EC 的记忆性 CCR6+ T 细胞中存在 HIV-DNA 与 HIV 限制因子(SERINC3、KLF3 和 RNF125)和 HIV 抑制因子(tetraspanins)的下调以及 HIV 依赖因子 MRE11 的表达增加相对应,表明对 HIV-1 感染的易感性/容许度更高。此外,与 HDs 相比,STs 和 ECs 的记忆性 CCR6+ T 细胞的 DNA 损伤/修饰标记物升高,这与它们的活化(CD38/HLA-DR)、衰老/衰竭表型(CTLA-4/PD-1/CD57)增加以及增殖标记物 Ki-67 表达减少相一致:这些结果揭示了ST和EC PWH中Th17细胞缺失的新分子机制,尽管它们成功地控制了HIV-1的复制。这些知识为限制HIV-1感染、恢复Th17细胞的频率、效应功能和衰老/衰竭的潜在治疗干预指明了方向:本研究由加拿大卫生研究院(CIHR,业务资助 MOP 142294 和加拿大 HIV 治愈企业 [CanCURE 2.0] 团队资助 HB2 164064)资助,并部分由魁北克-圣地研究基金会 SIDA 和感染性疾病网络(FRQ-S)资助。
{"title":"Altered memory CCR6<sup>+</sup> Th17-polarised T-cell function and biology in people with HIV under successful antiretroviral therapy and HIV elite controllers.","authors":"Alexis Yero, Jean-Philippe Goulet, Tao Shi, Cecilia T Costiniuk, Jean-Pierre Routy, Cecile Tremblay, Ralph-Sydney Mboumba Bouassa, Yulia Alexandrova, Amélie Pagliuzza, Nicolas Chomont, Petronela Ancuta, Mohammad-Ali Jenabian","doi":"10.1016/j.ebiom.2024.105274","DOIUrl":"https://doi.org/10.1016/j.ebiom.2024.105274","url":null,"abstract":"<p><strong>Background: </strong>Despite successful antiretroviral therapy (ART), frequencies and immunological functions of memory CCR6<sup>+</sup> Th17-polarised CD4<sup>+</sup> T-cells are not fully restored in people with HIV (PWH). Moreover, long-lived Th17 cells contribute to HIV persistence under ART. However, the molecular mechanisms underlying these observations remain understudied.</p><p><strong>Methods: </strong>mRNA-sequencing was performed using Illumina technology on freshly FACS-sorted memory CCR6<sup>+</sup>CD4<sup>+</sup> T-cells from successfully ART-treated (ST), elite controllers (EC), and uninfected donors (HD). Gene expression validation was performed by RT-PCR, flow cytometry, and in vitro functional assays.</p><p><strong>Findings: </strong>Decreased Th17 cell frequencies in STs and ECs versus HDs coincided with reduced Th17-lineage cytokine production in vitro. Accordingly, the RORγt/RORC2 repressor NR1D1 was upregulated, while the RORγt/RORC2 inducer Semaphorin 4D was decreased in memory CCR6<sup>+</sup> T-cells of STs and ECs versus HDs. The presence of HIV-DNA in memory CCR6<sup>+</sup> T-cells of ST and EC corresponded with the downregulation of HIV restriction factors (SERINC3, KLF3, and RNF125) and HIV inhibitors (tetraspanins), along with increased expression of the HIV-dependency factor MRE11, indicative of higher susceptibility/permissiveness to HIV-1 infection. Furthermore, markers of DNA damage/modification were elevated in memory CCR6<sup>+</sup> T-cells of STs and ECs versus HDs, in line with their increased activation (CD38/HLA-DR), senescence/exhaustion phenotype (CTLA-4/PD-1/CD57) and their decreased expression of proliferation marker Ki-67.</p><p><strong>Interpretation: </strong>These results reveal new molecular mechanisms of Th17 cell deficit in ST and EC PWH despite a successful control of HIV-1 replication. This knowledge points to potential therapeutic interventions to limit HIV-1 infection and restore frequencies, effector functions, and senescence/exhaustion in Th17 cells.</p><p><strong>Funding: </strong>This study was funded by the Canadian Institutes of Health Research (CIHR, operating grant MOP 142294, and the Canadian HIV Cure Enterprise [CanCURE 2.0] Team Grant HB2 164064), and in part, by the Réseau SIDA et maladies infectieuses du Fonds de recherche du Québec-Santé (FRQ-S).</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":null,"pages":null},"PeriodicalIF":9.7,"publicationDate":"2024-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142046497","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}
Pub Date : 2024-08-22DOI: 10.1016/j.ebiom.2024.105253
Leen Rasking, Thessa Van Pee, Maartje Vangeneugden, Eleni Renaers, Congrong Wang, Joris Penders, Katrien De Vusser, Michelle Plusquin, Tim S Nawrot
Background: Nephron number variability may hold significance in the Developmental Origins of Health and Disease hypothesis. We explore the impact of gestational particulate pollution exposure on cord blood cystatin C, a marker for glomerular function, as an indicator for glomerular health at birth.
Methods: From February 2010 onwards, the ENVIRONAGE cohort includes over 2200 mothers giving birth at the East-Limburg hospital in Genk, Belgium. Mothers without planned caesarean section who are able to fill out a Dutch questionnaire are eligible. Here, we evaluated cord blood cystatin C levels from 1484 mother-child pairs participating in the ENVIRONAGE cohort. We employed multiple linear regression models and distributed lag models to assess the association between cord blood cystatin C and gestational particulate air pollution exposure.
Findings: Average ± SD levels of cord blood cystatin C levels amounted to 2.16 ± 0.35 mg/L. Adjusting for covariates, every 0.5 μg/m³ and 5 μg/m³ increment in gestational exposure to black carbon (BC) and fine particulate matter (PM2.5) corresponded to increases of 0.04 mg/L (95% CI 0.01-0.07) and 0.07 mg/L (95% CI 0.03-0.11) in cord blood cystatin C levels (p < 0.01), respectively. Third-trimester exposure showed similar associations, with a 0.04 mg/L (95% CI 0.00-0.08) and 0.06 mg/L (95% CI 0.04-0.09) increase for BC and PM2.5 (p < 0.02). No significant associations were observed when considering only the first and second trimester exposure.
Interpretation: Our findings indicate that particulate air pollution during the entire pregnancy, with the strongest effect sizes from week 27 onwards, may affect newborn kidney function, with potential long-term implications for later health.
Funding: Special Research Fund (Bijzonder Onderzoeksfonds, BOF), Flemish Scientific Research Fund (Fonds Wetenschappelijk Onderzoek, FWO), and Methusalem.
背景:肾小球数量变异在健康和疾病的发育起源假说中可能具有重要意义。我们探讨了妊娠期微粒污染暴露对脐带血胱抑素 C(肾小球功能的标志物)的影响,以此作为出生时肾小球健康的指标:从 2010 年 2 月起,ENVIRONAGE 队列包括 2200 多名在比利时根克市东林堡医院分娩的母亲。未计划剖腹产且能填写荷兰语问卷的母亲均符合条件。在此,我们对参与 ENVIRONAGE 队列的 1484 对母婴的脐带血胱抑素 C 水平进行了评估。我们采用多元线性回归模型和分布滞后模型来评估脐带血胱抑素 C 与妊娠期微粒空气污染暴露之间的关系:结果:脐带血胱抑素 C 的平均(± SD)水平为 2.16 ± 0.35 mg/L。调整协变量后,妊娠期黑碳(BC)和细颗粒物(PM2.5)暴露量每增加 0.5 μg/m³ 和 5 μg/m³,脐带血胱抑素 C 水平相应增加 0.04 mg/L(95% CI 0.01-0.07)和 0.07 mg/L(95% CI 0.03-0.11)(p 2.5):我们的研究结果表明,整个孕期的颗粒物空气污染可能会影响新生儿的肾功能,第27周以后的影响最大,并可能对日后的健康产生长期影响:特别研究基金(Bijzonder Onderzoeksfonds, BOF)、佛兰德科学研究基金(Fonds Wetenschappelijk Onderzoek, FWO)和 Methusalem。
{"title":"Newborn glomerular function and gestational particulate air pollution.","authors":"Leen Rasking, Thessa Van Pee, Maartje Vangeneugden, Eleni Renaers, Congrong Wang, Joris Penders, Katrien De Vusser, Michelle Plusquin, Tim S Nawrot","doi":"10.1016/j.ebiom.2024.105253","DOIUrl":"https://doi.org/10.1016/j.ebiom.2024.105253","url":null,"abstract":"<p><strong>Background: </strong>Nephron number variability may hold significance in the Developmental Origins of Health and Disease hypothesis. We explore the impact of gestational particulate pollution exposure on cord blood cystatin C, a marker for glomerular function, as an indicator for glomerular health at birth.</p><p><strong>Methods: </strong>From February 2010 onwards, the ENVIRONAGE cohort includes over 2200 mothers giving birth at the East-Limburg hospital in Genk, Belgium. Mothers without planned caesarean section who are able to fill out a Dutch questionnaire are eligible. Here, we evaluated cord blood cystatin C levels from 1484 mother-child pairs participating in the ENVIRONAGE cohort. We employed multiple linear regression models and distributed lag models to assess the association between cord blood cystatin C and gestational particulate air pollution exposure.</p><p><strong>Findings: </strong>Average ± SD levels of cord blood cystatin C levels amounted to 2.16 ± 0.35 mg/L. Adjusting for covariates, every 0.5 μg/m³ and 5 μg/m³ increment in gestational exposure to black carbon (BC) and fine particulate matter (PM<sub>2.5</sub>) corresponded to increases of 0.04 mg/L (95% CI 0.01-0.07) and 0.07 mg/L (95% CI 0.03-0.11) in cord blood cystatin C levels (p < 0.01), respectively. Third-trimester exposure showed similar associations, with a 0.04 mg/L (95% CI 0.00-0.08) and 0.06 mg/L (95% CI 0.04-0.09) increase for BC and PM<sub>2.5</sub> (p < 0.02). No significant associations were observed when considering only the first and second trimester exposure.</p><p><strong>Interpretation: </strong>Our findings indicate that particulate air pollution during the entire pregnancy, with the strongest effect sizes from week 27 onwards, may affect newborn kidney function, with potential long-term implications for later health.</p><p><strong>Funding: </strong>Special Research Fund (Bijzonder Onderzoeksfonds, BOF), Flemish Scientific Research Fund (Fonds Wetenschappelijk Onderzoek, FWO), and Methusalem.</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":null,"pages":null},"PeriodicalIF":9.7,"publicationDate":"2024-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142046466","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}
Pub Date : 2024-08-22DOI: 10.1016/j.ebiom.2024.105295
Adrian Madarasz, Li Xin, Steven T Proulx
Background: Atraumatic subarachnoid haemorrhage (SAH) is associated with high morbidity and mortality. Proposed mechanisms for red blood cell (RBC) clearance from the subarachnoid space (SAS) are erythrolysis, erythrophagocytosis or through efflux along cerebrospinal fluid (CSF) drainage routes. We aimed to elucidate the mechanisms of RBC clearance from the SAS to identify targetable efflux pathways.
Methods: Autologous fluorescently-labelled RBCs along with PEGylated 40 kDa near-infrared tracer (P40D800) were infused via the cisterna magna (i.c.m.) in female reporter mice for lymphatics or for resident phagocytes. Drainage pathways for RBCs to extracranial lymphatics were evaluated by in vivo and in situ near-infrared imaging and by immunofluorescent staining on decalcified cranial tissue or dural whole-mounts.
Findings: RBCs drained to the deep cervical lymph nodes 15 min post i.c.m. infusion, showing similar dynamics as P40D800 tracer. Postmortem in situ imaging and histology showed perineural accumulations of RBCs around the optic and olfactory nerves. Numerous RBCs cleared through the lymphatics of the cribriform plate, whilst histology showed no relevant fast RBC clearance through dorsal dural lymphatics or by tissue-resident macrophage-mediated phagocytosis.
Interpretation: This study provides evidence for rapid RBC drainage through the cribriform plate lymphatic vessels, whilst neither fast RBC clearance through dorsal dural lymphatics nor through spinal CSF efflux or phagocytosis was observed. Similar dynamics of P40D800 and RBCs imply open pathways for clearance that do not impose a barrier for RBCs. This finding suggests further evaluation of the cribriform plate lymphatic function and potential pharmacological targeting in models of SAH.
Funding: Swiss National Science Foundation (310030_189226), SwissHeart (FF191155).
{"title":"Clearance of erythrocytes from the subarachnoid space through cribriform plate lymphatics in female mice.","authors":"Adrian Madarasz, Li Xin, Steven T Proulx","doi":"10.1016/j.ebiom.2024.105295","DOIUrl":"https://doi.org/10.1016/j.ebiom.2024.105295","url":null,"abstract":"<p><strong>Background: </strong>Atraumatic subarachnoid haemorrhage (SAH) is associated with high morbidity and mortality. Proposed mechanisms for red blood cell (RBC) clearance from the subarachnoid space (SAS) are erythrolysis, erythrophagocytosis or through efflux along cerebrospinal fluid (CSF) drainage routes. We aimed to elucidate the mechanisms of RBC clearance from the SAS to identify targetable efflux pathways.</p><p><strong>Methods: </strong>Autologous fluorescently-labelled RBCs along with PEGylated 40 kDa near-infrared tracer (P40D800) were infused via the cisterna magna (i.c.m.) in female reporter mice for lymphatics or for resident phagocytes. Drainage pathways for RBCs to extracranial lymphatics were evaluated by in vivo and in situ near-infrared imaging and by immunofluorescent staining on decalcified cranial tissue or dural whole-mounts.</p><p><strong>Findings: </strong>RBCs drained to the deep cervical lymph nodes 15 min post i.c.m. infusion, showing similar dynamics as P40D800 tracer. Postmortem in situ imaging and histology showed perineural accumulations of RBCs around the optic and olfactory nerves. Numerous RBCs cleared through the lymphatics of the cribriform plate, whilst histology showed no relevant fast RBC clearance through dorsal dural lymphatics or by tissue-resident macrophage-mediated phagocytosis.</p><p><strong>Interpretation: </strong>This study provides evidence for rapid RBC drainage through the cribriform plate lymphatic vessels, whilst neither fast RBC clearance through dorsal dural lymphatics nor through spinal CSF efflux or phagocytosis was observed. Similar dynamics of P40D800 and RBCs imply open pathways for clearance that do not impose a barrier for RBCs. This finding suggests further evaluation of the cribriform plate lymphatic function and potential pharmacological targeting in models of SAH.</p><p><strong>Funding: </strong>Swiss National Science Foundation (310030_189226), SwissHeart (FF191155).</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":null,"pages":null},"PeriodicalIF":9.7,"publicationDate":"2024-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142046463","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}