Xiaoyan Deng, Pierre Gantner, Julia Forestell, Amélie Pagliuzza, Elsa Brunet-Ratnasingham, Madeleine Durand, Daniel E Kaufmann, Nicolas Chomont, Morgan Craig
Objectives
Identifying biomarkers causing differential SARS-CoV-2 infection kinetics associated with severe COVID-19 is fundamental for effective diagnostics and therapeutic planning.
Methods
In this work, we applied mathematical modelling to investigate the relationships between patient characteristics, plasma SARS-CoV-2 RNA dynamics and COVID-19 severity. Using a straightforward mathematical model of within-host viral kinetics, we estimated key model parameters from serial plasma viral RNA (vRNA) samples from 256 hospitalised COVID-19+ patients.
Results
Our model predicted that clearance rates distinguish key differences in plasma vRNA kinetics and severe COVID-19. Moreover, our analyses revealed a strong correlation between plasma vRNA kinetics and plasma receptor for advanced glycation end products (RAGE) concentrations (a plasma biomarker of lung damage), collected in parallel to plasma vRNA from patients in our cohort, suggesting that RAGE can substitute for viral plasma shedding dynamics to prospectively classify seriously ill patients.
Conclusion
Overall, our study identifies factors of COVID-19 severity, supports interventions to accelerate viral clearance and underlines the importance of mathematical modelling to better understand COVID-19.
{"title":"Plasma SARS-CoV-2 RNA elimination and RAGE kinetics distinguish COVID-19 severity","authors":"Xiaoyan Deng, Pierre Gantner, Julia Forestell, Amélie Pagliuzza, Elsa Brunet-Ratnasingham, Madeleine Durand, Daniel E Kaufmann, Nicolas Chomont, Morgan Craig","doi":"10.1002/cti2.1468","DOIUrl":"https://doi.org/10.1002/cti2.1468","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objectives</h3>\u0000 \u0000 <p>Identifying biomarkers causing differential SARS-CoV-2 infection kinetics associated with severe COVID-19 is fundamental for effective diagnostics and therapeutic planning.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>In this work, we applied mathematical modelling to investigate the relationships between patient characteristics, plasma SARS-CoV-2 RNA dynamics and COVID-19 severity. Using a straightforward mathematical model of within-host viral kinetics, we estimated key model parameters from serial plasma viral RNA (vRNA) samples from 256 hospitalised COVID-19<sup>+</sup> patients.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Our model predicted that clearance rates distinguish key differences in plasma vRNA kinetics and severe COVID-19. Moreover, our analyses revealed a strong correlation between plasma vRNA kinetics and plasma receptor for advanced glycation end products (RAGE) concentrations (a plasma biomarker of lung damage), collected in parallel to plasma vRNA from patients in our cohort, suggesting that RAGE can substitute for viral plasma shedding dynamics to prospectively classify seriously ill patients.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Overall, our study identifies factors of COVID-19 severity, supports interventions to accelerate viral clearance and underlines the importance of mathematical modelling to better understand COVID-19.</p>\u0000 </section>\u0000 </div>","PeriodicalId":152,"journal":{"name":"Clinical & Translational Immunology","volume":"12 11","pages":""},"PeriodicalIF":5.8,"publicationDate":"2023-11-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cti2.1468","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138432502","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Hyunjung Min, Laura A Valente, Li Xu, Shane M O'Neil, Lauren R Begg, Joanne Kurtzberg, Anthony J Filiano
<div> <section> <h3> Objectives</h3> <p>Thymus implantation is a recently FDA-approved therapy for congenital athymia. Patients receiving thymus implantation develop a functional but incomplete T cell compartment. Our objective was to develop a mouse model to study clinical thymus implantation in congenital athymia and to optimise implantation procedures to maximise T cell education and expansion of naïve T cells.</p> </section> <section> <h3> Methods</h3> <p>Using <i>Foxn1</i><sup>nu</sup> athymic mice as recipients, we tested MHC-matched and -mismatched donor thymi that were implanted as fresh tissue or cultured to remove donor T cells. We first implanted thymus under the kidney capsule and then optimised intramuscular implantation. Using competitive adoptive transfer assays, we investigated whether the failure of newly developed T cells to expand into a complete T cell compartment was because of intrinsic deficits or whether there were deficits in engaging MHC molecules in the periphery. Finally, we tested whether recombinant IL-7 would promote the expansion of host naïve T cells educated by the implanted thymus.</p> </section> <section> <h3> Results</h3> <p>We determined that thymus implants in <i>Foxn1</i><sup>nu</sup> athymic mice mimic many aspects of clinical thymus implants in patients with congenital athymia. When we implanted cultured, MHC-mismatched donor thymus into <i>Foxn1</i><sup>nu</sup> athymic mice, mice developed a limited T cell compartment with notably underdeveloped naïve populations and overrepresented memory-like T cells. Newly generated T cells were predominantly educated by MHC molecules expressed by the donor thymus, thus potentially undergoing another round of selection once in the peripheral circulation. Using competitive adoptive transfer assays, we compared expansion rates of T cells educated on donor thymus <i>versus</i> T cells educated during typical thymopoiesis in MHC-matched and -mismatched environments. Once in the circulation, regardless of the MHC haplotypes, T cells educated on a donor thymus underwent abnormal expansion with initially more robust proliferation coupled with greater cell death, resembling IL-7 independent spontaneous expansion. Treating implanted mice with recombinant interleukin (IL-7) promoted homeostatic expansion that improved T cell development, expanded the T cell receptor repertoire, and normalised the naïve T cell compartment.</p> </section> <section> <h3> Conclusion</h3> <p>We conclude that implanting cultured thymus into the muscle of <i>Foxn1</i><sup>nu</sup> athymic mice is an ap
{"title":"Improving thymus implantation for congenital athymia with interleukin-7","authors":"Hyunjung Min, Laura A Valente, Li Xu, Shane M O'Neil, Lauren R Begg, Joanne Kurtzberg, Anthony J Filiano","doi":"10.1002/cti2.1475","DOIUrl":"https://doi.org/10.1002/cti2.1475","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objectives</h3>\u0000 \u0000 <p>Thymus implantation is a recently FDA-approved therapy for congenital athymia. Patients receiving thymus implantation develop a functional but incomplete T cell compartment. Our objective was to develop a mouse model to study clinical thymus implantation in congenital athymia and to optimise implantation procedures to maximise T cell education and expansion of naïve T cells.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Using <i>Foxn1</i><sup>nu</sup> athymic mice as recipients, we tested MHC-matched and -mismatched donor thymi that were implanted as fresh tissue or cultured to remove donor T cells. We first implanted thymus under the kidney capsule and then optimised intramuscular implantation. Using competitive adoptive transfer assays, we investigated whether the failure of newly developed T cells to expand into a complete T cell compartment was because of intrinsic deficits or whether there were deficits in engaging MHC molecules in the periphery. Finally, we tested whether recombinant IL-7 would promote the expansion of host naïve T cells educated by the implanted thymus.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>We determined that thymus implants in <i>Foxn1</i><sup>nu</sup> athymic mice mimic many aspects of clinical thymus implants in patients with congenital athymia. When we implanted cultured, MHC-mismatched donor thymus into <i>Foxn1</i><sup>nu</sup> athymic mice, mice developed a limited T cell compartment with notably underdeveloped naïve populations and overrepresented memory-like T cells. Newly generated T cells were predominantly educated by MHC molecules expressed by the donor thymus, thus potentially undergoing another round of selection once in the peripheral circulation. Using competitive adoptive transfer assays, we compared expansion rates of T cells educated on donor thymus <i>versus</i> T cells educated during typical thymopoiesis in MHC-matched and -mismatched environments. Once in the circulation, regardless of the MHC haplotypes, T cells educated on a donor thymus underwent abnormal expansion with initially more robust proliferation coupled with greater cell death, resembling IL-7 independent spontaneous expansion. Treating implanted mice with recombinant interleukin (IL-7) promoted homeostatic expansion that improved T cell development, expanded the T cell receptor repertoire, and normalised the naïve T cell compartment.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>We conclude that implanting cultured thymus into the muscle of <i>Foxn1</i><sup>nu</sup> athymic mice is an ap","PeriodicalId":152,"journal":{"name":"Clinical & Translational Immunology","volume":"12 11","pages":""},"PeriodicalIF":5.8,"publicationDate":"2023-11-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cti2.1475","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138431978","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Ebene R Haycroft, Timon Damelang, Ester Lopez, Mark A Rodgers, Bruce D Wines, Mark Hogarth, Cassaundra L Ameel, Stephen J Kent, Charles A Scanga, Shelby L O'Connor, Amy W Chung
Objectives
Tuberculosis (TB) remains a substantial cause of morbidity and mortality among people living with human immunodeficiency virus (HIV) worldwide. However, the immunological mechanisms associated with the enhanced susceptibility among HIV-positive individuals remain largely unknown.
Methods
Here, we used a simian immunodeficiency virus (SIV)/TB-coinfection Mauritian cynomolgus macaque (MCM) model to examine humoral responses from the plasma of SIV-negative (n = 8) and SIV-positive (n = 7) MCM 8-week postinfection with Mycobacterium tuberculosis (Mtb).
Results
Antibody responses to Mtb were impaired during SIV coinfection. Elevated inflammatory bulk IgG antibody glycosylation patterns were observed in coinfected macaques early at 8-week post-Mtb infection, including increased agalactosylation (G0) and reduced di-galactosylation (G2), which correlated with endpoint Mtb bacterial burden and gross pathology scores, as well as the time-to-necropsy.
Conclusion
These studies suggest that humoral immunity may contribute to control of TB disease and support growing literature that highlights antibody Fc glycosylation as a biomarker of TB disease progression.
{"title":"Antibody glycosylation correlates with disease progression in SIV-Mycobacterium tuberculosis coinfected cynomolgus macaques","authors":"Ebene R Haycroft, Timon Damelang, Ester Lopez, Mark A Rodgers, Bruce D Wines, Mark Hogarth, Cassaundra L Ameel, Stephen J Kent, Charles A Scanga, Shelby L O'Connor, Amy W Chung","doi":"10.1002/cti2.1474","DOIUrl":"https://doi.org/10.1002/cti2.1474","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objectives</h3>\u0000 \u0000 <p>Tuberculosis (TB) remains a substantial cause of morbidity and mortality among people living with human immunodeficiency virus (HIV) worldwide. However, the immunological mechanisms associated with the enhanced susceptibility among HIV-positive individuals remain largely unknown.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Here, we used a simian immunodeficiency virus (SIV)/TB-coinfection Mauritian cynomolgus macaque (MCM) model to examine humoral responses from the plasma of SIV-negative (<i>n</i> = 8) and SIV-positive (<i>n</i> = 7) MCM 8-week postinfection with <i>Mycobacterium tuberculosis</i> (<i>Mtb</i>).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Antibody responses to <i>Mtb</i> were impaired during SIV coinfection. Elevated inflammatory bulk IgG antibody glycosylation patterns were observed in coinfected macaques early at 8-week post-<i>Mtb</i> infection, including increased agalactosylation (G0) and reduced di-galactosylation (G2), which correlated with endpoint <i>Mtb</i> bacterial burden and gross pathology scores, as well as the time-to-necropsy.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>These studies suggest that humoral immunity may contribute to control of TB disease and support growing literature that highlights antibody Fc glycosylation as a biomarker of TB disease progression.</p>\u0000 </section>\u0000 </div>","PeriodicalId":152,"journal":{"name":"Clinical & Translational Immunology","volume":"12 11","pages":""},"PeriodicalIF":5.8,"publicationDate":"2023-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cti2.1474","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138432372","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Jonas Saal, Jörg Ellinger, Manuel Ritter, Peter Brossart, Michael Hölzel, Niklas Klümper, Tobias Bald
Objectives
Reliable predictive biomarkers for response to immune checkpoint inhibition (ICI) are lacking. Pretreatment serum albumin, a known prognostic and predictive factor in ICI-treated patients, has been proposed as a potential pharmacokinetic surrogate marker for anti-PD1/PD-L1 antibodies, as it shares a homeostatic pathway with IgG. However, this hypothesis is currently based on theoretical considerations and limited evidence from retrospective data. Therefore, we comprehensively investigated the prognostic and predictive value of pretreatment albumin and its relationship with anti-PD-L1 IgG levels.
Methods
We analysed pretreatment albumin and atezolizumab serum levels and clinical response in four trials (IMvigor210, IMvigor211, IMmotion151 and OAK) of patients with metastatic lung-, renal- or urothelial cancer who received atezolizumab alone or in combination.
Results
A total of 3391 patients were analysed. Correlation between serum albumin and atezolizumab levels was weak (Pearson's coefficient 0.23). We found a strong prognostic value for pretreatment serum albumin across all trials. Both atezolizumab serum levels and serum albumin were independently correlated with overall survival. Importantly, in the three randomised phase III clinical trials, the survival benefit for immunotherapy compared with the active comparator arm was limited to patients with pretreatment serum albumin > 35 g L−1.
Conclusion
Our data do not support the hypothesis that albumin serves as a surrogate for atezolizumab pharmacokinetics. However, we show that albumin on its own exerts strong prognostic value for patients treated with immunotherapy. As benefit from immunotherapy was limited to patients with normal/elevated serum albumin levels, baseline albumin could potentially be used as a predictive marker for immune checkpoint inhibition.
{"title":"Pretreatment albumin is a prognostic and predictive biomarker for response to atezolizumab across solid tumors","authors":"Jonas Saal, Jörg Ellinger, Manuel Ritter, Peter Brossart, Michael Hölzel, Niklas Klümper, Tobias Bald","doi":"10.1002/cti2.1472","DOIUrl":"10.1002/cti2.1472","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objectives</h3>\u0000 \u0000 <p>Reliable predictive biomarkers for response to immune checkpoint inhibition (ICI) are lacking. Pretreatment serum albumin, a known prognostic and predictive factor in ICI-treated patients, has been proposed as a potential pharmacokinetic surrogate marker for anti-PD1/PD-L1 antibodies, as it shares a homeostatic pathway with IgG. However, this hypothesis is currently based on theoretical considerations and limited evidence from retrospective data. Therefore, we comprehensively investigated the prognostic and predictive value of pretreatment albumin and its relationship with anti-PD-L1 IgG levels.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We analysed pretreatment albumin and atezolizumab serum levels and clinical response in four trials (IMvigor210, IMvigor211, IMmotion151 and OAK) of patients with metastatic lung-, renal- or urothelial cancer who received atezolizumab alone or in combination.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>A total of 3391 patients were analysed. Correlation between serum albumin and atezolizumab levels was weak (Pearson's coefficient 0.23). We found a strong prognostic value for pretreatment serum albumin across all trials. Both atezolizumab serum levels and serum albumin were independently correlated with overall survival. Importantly, in the three randomised phase III clinical trials, the survival benefit for immunotherapy compared with the active comparator arm was limited to patients with pretreatment serum albumin > 35 g L<sup>−1</sup>.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Our data do not support the hypothesis that albumin serves as a surrogate for atezolizumab pharmacokinetics. However, we show that albumin on its own exerts strong prognostic value for patients treated with immunotherapy. As benefit from immunotherapy was limited to patients with normal/elevated serum albumin levels, baseline albumin could potentially be used as a predictive marker for immune checkpoint inhibition.</p>\u0000 </section>\u0000 </div>","PeriodicalId":152,"journal":{"name":"Clinical & Translational Immunology","volume":"12 11","pages":""},"PeriodicalIF":5.8,"publicationDate":"2023-11-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10632074/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"72012782","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Katharine A Kott, Adam S Chan, Stephen T Vernon, Thomas Hansen, Taiyun Kim, Macha de Dreu, Bavani Gunasegaran, Andrew J Murphy, Ellis Patrick, Peter J Psaltis, Stuart M Grieve, Jean Y Yang, Barbara Fazekas de St Groth, Helen M McGuire, Gemma A Figtree
Objective
The importance of inflammation in atherosclerosis is well accepted, but the role of the adaptive immune system is not yet fully understood. To further explore this, we assessed the circulating immune cell profile of patients with coronary artery disease (CAD) to identify discriminatory features by mass cytometry.
Methods
Mass cytometry was performed on patient samples from the BioHEART-CT study, gated to detect 82 distinct cell subsets. CT coronary angiograms were analysed to categorise patients as having CAD (CAD+) or having normal coronary arteries (CAD−).
Results
The discovery cohort included 117 patients (mean age 61 ± 12 years, 49% female); 79 patients (68%) were CAD+. Mass cytometry identified changes in 15 T-cell subsets, with higher numbers of proliferating, highly differentiated and cytotoxic cells and decreases in naïve T cells. Five T-regulatory subsets were related to an age and gender-independent increase in the odds of CAD incidence when expressing CCR2 (OR 1.12), CCR4 (OR 1.08), CD38 and CD45RO (OR 1.13), HLA-DR (OR 1.06) and Ki67 (OR 1.22). Markers of proliferation and differentiation were also increased within B cells, while plasmacytoid dendritic cells were decreased. This combination of changes was assessed using SVM models in discovery and validation cohorts (area under the curve = 0.74 for both), confirming the robust nature of the immune signature detected.
Conclusion
We identified differences within immune subpopulations of CAD+ patients which are indicative of a systemic immune response to coronary atherosclerosis. This immune signature needs further study via incorporation into risk scoring tools for the precision diagnosis of CAD.
{"title":"Mass cytometry analysis reveals altered immune profiles in patients with coronary artery disease","authors":"Katharine A Kott, Adam S Chan, Stephen T Vernon, Thomas Hansen, Taiyun Kim, Macha de Dreu, Bavani Gunasegaran, Andrew J Murphy, Ellis Patrick, Peter J Psaltis, Stuart M Grieve, Jean Y Yang, Barbara Fazekas de St Groth, Helen M McGuire, Gemma A Figtree","doi":"10.1002/cti2.1462","DOIUrl":"10.1002/cti2.1462","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objective</h3>\u0000 \u0000 <p>The importance of inflammation in atherosclerosis is well accepted, but the role of the adaptive immune system is not yet fully understood. To further explore this, we assessed the circulating immune cell profile of patients with coronary artery disease (CAD) to identify discriminatory features by mass cytometry.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Mass cytometry was performed on patient samples from the BioHEART-CT study, gated to detect 82 distinct cell subsets. CT coronary angiograms were analysed to categorise patients as having CAD (CAD<sup>+</sup>) or having normal coronary arteries (CAD<sup>−</sup>).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>The discovery cohort included 117 patients (mean age 61 ± 12 years, 49% female); 79 patients (68%) were CAD<sup>+</sup>. Mass cytometry identified changes in 15 T-cell subsets, with higher numbers of proliferating, highly differentiated and cytotoxic cells and decreases in naïve T cells. Five T-regulatory subsets were related to an age and gender-independent increase in the odds of CAD incidence when expressing CCR2 (OR 1.12), CCR4 (OR 1.08), CD38 and CD45RO (OR 1.13), HLA-DR (OR 1.06) and Ki67 (OR 1.22). Markers of proliferation and differentiation were also increased within B cells, while plasmacytoid dendritic cells were decreased. This combination of changes was assessed using SVM models in discovery and validation cohorts (area under the curve = 0.74 for both), confirming the robust nature of the immune signature detected.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>We identified differences within immune subpopulations of CAD<sup>+</sup> patients which are indicative of a systemic immune response to coronary atherosclerosis. This immune signature needs further study <i>via</i> incorporation into risk scoring tools for the precision diagnosis of CAD.</p>\u0000 </section>\u0000 </div>","PeriodicalId":152,"journal":{"name":"Clinical & Translational Immunology","volume":"12 11","pages":""},"PeriodicalIF":5.8,"publicationDate":"2023-11-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"71475943","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Benedikt Hoeh, Cristina Cano Garcia, Severine Banek, Niklas Klümper, Alexander Cox, Jörg Ellinger, Philipp Schmucker, Oliver Hahn, Angelika Mattigk, Friedemann Zengerling, Philippe Becker, Kati Erdmann, Bjoern Thorben Buerk, Luka Flegar, Johannes Huber, Charis Kalogirou, Philip Zeuschner
Objectives
Although biomarkers predicting therapy response in first-line metastatic renal carcinoma (mRCC) therapy remain to be defined, C-reactive protein (CRP) kinetics have recently been associated with immunotherapy (IO) response. Here, we aimed to assess the predictive and prognostic power of two contemporary CRP kinetics definitions in a large, real-world first-line mRCC cohort.
Methods
Metastatic renal carcinoma patients treated with IO-based first-line therapy within 5 years were retrospectively included in this multicentre study. According to Fukuda et al., patients were defined as ‘CRP flare-responder’, ‘CRP responder’ and ‘non-CRP responder’; according to Ishihara et al., patients were defined as ‘normal’, ‘normalised’ and ‘non-normalised’ based on their early CRP kinetics. Patient and tumor characteristics were compared, and treatment outcome was measured by overall (OS) and progression-free survival (PFS), including multivariable Cox regression analyses.
Results
Out of 316 mRCC patients, 227 (72%) were assigned to CRP groups according to Fukuda. Both CRP flare- (HR [Hazard ratio]: 0.59) and CRP responders (HR: 0.52) had a longer PFS, but not OS, than non-CRP responders. According to Ishihara, 276 (87%) patients were assigned to the respective groups, and both normal and normalised patients had a significantly longer PFS and OS, compared with non-normalised group.
Conclusion
Different early CRP kinetics may predict therapy response in first-line mRCC therapy in a large real-world cohort. However, further research regarding the optimal timing and frequency of measurement is needed.
{"title":"Early CRP kinetics to predict long-term efficacy of first-line immune-checkpoint inhibition combination therapies in metastatic renal cell carcinoma: an updated multicentre real-world experience applying different CRP kinetics definitions","authors":"Benedikt Hoeh, Cristina Cano Garcia, Severine Banek, Niklas Klümper, Alexander Cox, Jörg Ellinger, Philipp Schmucker, Oliver Hahn, Angelika Mattigk, Friedemann Zengerling, Philippe Becker, Kati Erdmann, Bjoern Thorben Buerk, Luka Flegar, Johannes Huber, Charis Kalogirou, Philip Zeuschner","doi":"10.1002/cti2.1471","DOIUrl":"10.1002/cti2.1471","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objectives</h3>\u0000 \u0000 <p>Although biomarkers predicting therapy response in first-line metastatic renal carcinoma (mRCC) therapy remain to be defined, C-reactive protein (CRP) kinetics have recently been associated with immunotherapy (IO) response. Here, we aimed to assess the predictive and prognostic power of two contemporary CRP kinetics definitions in a large, real-world first-line mRCC cohort.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Metastatic renal carcinoma patients treated with IO-based first-line therapy within 5 years were retrospectively included in this multicentre study. According to Fukuda <i>et al.</i>, patients were defined as ‘CRP flare-responder’, ‘CRP responder’ and ‘non-CRP responder’; according to Ishihara <i>et al.</i>, patients were defined as ‘normal’, ‘normalised’ and ‘non-normalised’ based on their early CRP kinetics. Patient and tumor characteristics were compared, and treatment outcome was measured by overall (OS) and progression-free survival (PFS), including multivariable Cox regression analyses.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Out of 316 mRCC patients, 227 (72%) were assigned to CRP groups according to Fukuda. Both CRP flare- (HR [Hazard ratio]: 0.59) and CRP responders (HR: 0.52) had a longer PFS, but not OS, than non-CRP responders. According to Ishihara, 276 (87%) patients were assigned to the respective groups, and both normal and normalised patients had a significantly longer PFS and OS, compared with non-normalised group.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Different early CRP kinetics may predict therapy response in first-line mRCC therapy in a large real-world cohort. However, further research regarding the optimal timing and frequency of measurement is needed.</p>\u0000 </section>\u0000 </div>","PeriodicalId":152,"journal":{"name":"Clinical & Translational Immunology","volume":"12 10","pages":""},"PeriodicalIF":5.8,"publicationDate":"2023-10-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10600333/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"71409921","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Jack Polmear, Lauren Hailes, Moshe Olshansky, Maureen Rischmueller, Elan L'Estrange-Stranieri, Anne L Fletcher, Margaret L Hibbs, Vanessa L Bryant, Kim L Good-Jacobson
Objectives
B cells drive the production of autoreactive antibody-secreting cells (ASCs) in autoimmune diseases such as Systemic Lupus Erythematosus (SLE) and Sjögren's syndrome, causing long-term organ damage. Current treatments for antibody-mediated autoimmune diseases target B cells or broadly suppress the immune system. However, pre-existing long-lived ASCs are often refractory to treatment, leaving a reservoir of autoreactive cells that continue to produce antibodies. Therefore, the development of novel treatment methods targeting ASCs is vital to improve patient outcomes. Our objective was to test whether targeting the epigenetic regulator BMI-1 could deplete ASCs in autoimmune conditions in vivo and in vitro.
Methods
Use of a BMI-1 inhibitor in both mouse and human autoimmune settings was investigated. Lyn−/− mice, a model of SLE, were treated with the BMI-1 small molecule inhibitor PTC-028, before assessment of ASCs, serum antibody and immune complexes. To examine human ASC survival, a novel human fibroblast-based assay was established, and the impact of PTC-028 on ASCs derived from Sjögren's syndrome patients was evaluated.
Results
BMI-1 inhibition significantly decreased splenic and bone marrow ASCs in Lyn−/− mice. The decline in ASCs was linked to aberrant cell cycle gene expression and led to a significant decrease in serum IgG3, immune complexes and anti-DNA IgG. PTC-028 was also efficacious in reducing ex vivo plasma cell survival from both Sjögren's syndrome patients and age-matched healthy donors.
Conclusion
These data provide evidence that inhibiting BMI-1 can deplete ASC in a variety of contexts and thus BMI-1 is a viable therapeutic target for antibody-mediated autoimmune diseases.
{"title":"Targeting BMI-1 to deplete antibody-secreting cells in autoimmunity","authors":"Jack Polmear, Lauren Hailes, Moshe Olshansky, Maureen Rischmueller, Elan L'Estrange-Stranieri, Anne L Fletcher, Margaret L Hibbs, Vanessa L Bryant, Kim L Good-Jacobson","doi":"10.1002/cti2.1470","DOIUrl":"10.1002/cti2.1470","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objectives</h3>\u0000 \u0000 <p>B cells drive the production of autoreactive antibody-secreting cells (ASCs) in autoimmune diseases such as Systemic Lupus Erythematosus (SLE) and Sjögren's syndrome, causing long-term organ damage. Current treatments for antibody-mediated autoimmune diseases target B cells or broadly suppress the immune system. However, pre-existing long-lived ASCs are often refractory to treatment, leaving a reservoir of autoreactive cells that continue to produce antibodies. Therefore, the development of novel treatment methods targeting ASCs is vital to improve patient outcomes. Our objective was to test whether targeting the epigenetic regulator BMI-1 could deplete ASCs in autoimmune conditions <i>in vivo</i> and <i>in vitro</i>.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Use of a BMI-1 inhibitor in both mouse and human autoimmune settings was investigated. <i>Lyn</i><sup><i>−/−</i></sup> mice, a model of SLE, were treated with the BMI-1 small molecule inhibitor PTC-028, before assessment of ASCs, serum antibody and immune complexes. To examine human ASC survival, a novel human fibroblast-based assay was established, and the impact of PTC-028 on ASCs derived from Sjögren's syndrome patients was evaluated.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>BMI-1 inhibition significantly decreased splenic and bone marrow ASCs in <i>Lyn</i><sup><i>−/−</i></sup> mice. The decline in ASCs was linked to aberrant cell cycle gene expression and led to a significant decrease in serum IgG3, immune complexes and anti-DNA IgG. PTC-028 was also efficacious in reducing <i>ex vivo</i> plasma cell survival from both Sjögren's syndrome patients and age-matched healthy donors.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>These data provide evidence that inhibiting BMI-1 can deplete ASC in a variety of contexts and thus BMI-1 is a viable therapeutic target for antibody-mediated autoimmune diseases.</p>\u0000 </section>\u0000 </div>","PeriodicalId":152,"journal":{"name":"Clinical & Translational Immunology","volume":"12 10","pages":""},"PeriodicalIF":5.8,"publicationDate":"2023-10-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10550498/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41093720","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Alessia Furgiuele, Frederico C Pereira, Stefano Martini, Franca Marino, Marco Cosentino
Parkinson's disease (PD) is a neurodegenerative disease affecting 7–10 million people worldwide. Currently, there is no treatment available to prevent or delay PD progression, partially due to the limited understanding of the pathological events which lead to the death of dopaminergic neurons in the substantia nigra in the brain, which is known to be the cause of PD symptoms. The current available treatments aim at compensating dopamine (DA) deficiency in the brain using its precursor levodopa, dopaminergic agonists and some indirect dopaminergic agents. The immune system is emerging as a critical player in PD. Therefore, immune-based approaches have recently been proposed to be used as potential antiparkinsonian agents. It has been well-known that dopaminergic pathways play a significant role in regulating immune responses in the brain. Although dopaminergic agents are the primary antiparkinsonian treatments, their immune regulatory effect has yet to be fully understood. The present review summarises the current available evidence of the immune regulatory effects of DA and its mimics and discusses dopaminergic agents as antiparkinsonian drugs. Based on the current understanding of their involvement in the regulation of neuroinflammation in PD, we propose that targeting immune pathways involved in PD pathology could offer a better treatment outcome for PD patients.
{"title":"Dopaminergic regulation of inflammation and immunity in Parkinson's disease: friend or foe?","authors":"Alessia Furgiuele, Frederico C Pereira, Stefano Martini, Franca Marino, Marco Cosentino","doi":"10.1002/cti2.1469","DOIUrl":"https://doi.org/10.1002/cti2.1469","url":null,"abstract":"<p>Parkinson's disease (PD) is a neurodegenerative disease affecting 7–10 million people worldwide. Currently, there is no treatment available to prevent or delay PD progression, partially due to the limited understanding of the pathological events which lead to the death of dopaminergic neurons in the <i>substantia nigra</i> in the brain, which is known to be the cause of PD symptoms. The current available treatments aim at compensating dopamine (DA) deficiency in the brain using its precursor levodopa, dopaminergic agonists and some indirect dopaminergic agents. The immune system is emerging as a critical player in PD. Therefore, immune-based approaches have recently been proposed to be used as potential antiparkinsonian agents. It has been well-known that dopaminergic pathways play a significant role in regulating immune responses in the brain. Although dopaminergic agents are the primary antiparkinsonian treatments, their immune regulatory effect has yet to be fully understood. The present review summarises the current available evidence of the immune regulatory effects of DA and its mimics and discusses dopaminergic agents as antiparkinsonian drugs. Based on the current understanding of their involvement in the regulation of neuroinflammation in PD, we propose that targeting immune pathways involved in PD pathology could offer a better treatment outcome for PD patients.</p>","PeriodicalId":152,"journal":{"name":"Clinical & Translational Immunology","volume":"12 10","pages":""},"PeriodicalIF":5.8,"publicationDate":"2023-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cti2.1469","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41084335","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Hao Kang, Hongjian Sun, Yang Yang, Zewen K Tuong, Minglei Shu, Yunbo Wei, Yu Zhang, Di Yu, Yong Tao
Objectives
Non-infectious uveitis is often secondary to systemic autoimmune diseases, with Behçet's disease (BD) and Vogt-Koyanagi-Harada disease (VKHD) as the two most common causes. Uveitis in BD and VKHD can show similar clinical manifestations, but the underlying immunopathogenesis remains unclear.
Methods
To understand immune landscapes in inflammatory eye tissues, we performed single-cell RNA paired with T cell receptor (TCR) sequencing of immune cell infiltrates in aqueous humour from six patients with BD (N = 3) and VKHD (N = 3) uveitis patients.
Results
Although T cells strongly infiltrated in both types of autoimmune uveitis, myeloid cells only significantly presented in BD uveitis but not in VKHD uveitis. Conversely, VKHD uveitis but not BD uveitis showed an overwhelming dominance by CD4+ T cells (> 80%) within the T cell population due to expansion of CD4+ T cell clusters with effector memory (Tem) phenotypes. Correspondingly, VKHD uveitis demonstrated a selective expansion of CD4+ T cell clones which were enriched in pro-inflammatory Granzyme H+ CD4+ Tem cluster and showed TCR and Th1 pathway activation. In contrast, BD uveitis showed a preferential expansion of CD8+ T cell clones in pro-inflammatory Granzyme H+ CD8+ Tem cluster, and pathway activation for cytoskeleton remodelling, cellular adhesion and cytotoxicity.
Conclusion
Single-cell analyses of ocular tissues reveal distinct landscapes of immune cell infiltration and T-cell clonal expansions between VKHD and BD uveitis. Preferential involvements of pro-inflammatory CD4+ Th1 cells in VKHD and cytotoxic CD8+ T cells in BD suggest a difference in disease immunopathogenesis and can guide precision disease management.
{"title":"Autoimmune uveitis in Behçet's disease and Vogt-Koyanagi-Harada disease differ in tissue immune infiltration and T cell clonality","authors":"Hao Kang, Hongjian Sun, Yang Yang, Zewen K Tuong, Minglei Shu, Yunbo Wei, Yu Zhang, Di Yu, Yong Tao","doi":"10.1002/cti2.1461","DOIUrl":"10.1002/cti2.1461","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objectives</h3>\u0000 \u0000 <p>Non-infectious uveitis is often secondary to systemic autoimmune diseases, with Behçet's disease (BD) and Vogt-Koyanagi-Harada disease (VKHD) as the two most common causes. Uveitis in BD and VKHD can show similar clinical manifestations, but the underlying immunopathogenesis remains unclear.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>To understand immune landscapes in inflammatory eye tissues, we performed single-cell RNA paired with T cell receptor (TCR) sequencing of immune cell infiltrates in aqueous humour from six patients with BD (<i>N</i> = 3) and VKHD (<i>N</i> = 3) uveitis patients.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Although T cells strongly infiltrated in both types of autoimmune uveitis, myeloid cells only significantly presented in BD uveitis but not in VKHD uveitis. Conversely, VKHD uveitis but not BD uveitis showed an overwhelming dominance by CD4<sup>+</sup> T cells (> 80%) within the T cell population due to expansion of CD4<sup>+</sup> T cell clusters with effector memory (Tem) phenotypes. Correspondingly, VKHD uveitis demonstrated a selective expansion of CD4<sup>+</sup> T cell clones which were enriched in pro-inflammatory Granzyme H<sup>+</sup> CD4<sup>+</sup> Tem cluster and showed TCR and Th1 pathway activation. In contrast, BD uveitis showed a preferential expansion of CD8<sup>+</sup> T cell clones in pro-inflammatory Granzyme H<sup>+</sup> CD8<sup>+</sup> Tem cluster, and pathway activation for cytoskeleton remodelling, cellular adhesion and cytotoxicity.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Single-cell analyses of ocular tissues reveal distinct landscapes of immune cell infiltration and T-cell clonal expansions between VKHD and BD uveitis. Preferential involvements of pro-inflammatory CD4<sup>+</sup> Th1 cells in VKHD and cytotoxic CD8<sup>+</sup> T cells in BD suggest a difference in disease immunopathogenesis and can guide precision disease management.</p>\u0000 </section>\u0000 </div>","PeriodicalId":152,"journal":{"name":"Clinical & Translational Immunology","volume":"12 9","pages":""},"PeriodicalIF":5.8,"publicationDate":"2023-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10503407/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10308461","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Naiqing Ding, Qin Liu, Juan Du, Jie Shao, Yang Yang, Ju Yang, Fangjun Chen, Lixia Yu, Baorui Liu, Jia Wei
Objectives
The signet-ring cell carcinoma (SRCC) of the stomach is highly invasive. Patients with stage III gastric SRCC usually experience tumor recurrence within 2 years after radical surgery. Unfortunately, there is no effective treatment to postpone recurrence following adjuvant chemotherapy. Our study aimed to explore the safety and efficacy of neoantigen-reactive T lymphocytes (NRTs) in patients with stage III gastric SRCC.
Methods
The study included 20 patients with stage III gastric SRCC who received radical surgery and adjuvant chemotherapy. Following the adjuvant chemotherapy, they underwent treatment with a range of one to four cycles of personalised neoantigen-reactive T cells. The primary endpoint was the median progression-free survival (mDFS). The secondary endpoint was safety and immune responses. The median duration of follow-up was 41 months (95% CI: 39–42.9 months).
Results
Our results showed that patients who received adjuvant neoantigen-reactive T-cell immunotherapy demonstrated a propensity towards prolonged disease-free survival (DFS) and overall survival (OS) in comparison to previous studies. The 2-year DFS and OS rates reached 73.7% and 95%, respectively, whereas the 5-year DFS and OS rates were 44% and 69%. The median DFS was 41 months (95% CI: 28.9–53.1 months) and the median OS was not reached. In addition, there was a significant increase in serum concentrations of IL-2, IL-4, IL-6, IL-10, TNF-α and IFN-γ after cell immunotherapy. The adverse reactions were mild.
Conclusion
In conclusion, adjuvant immunotherapy with NRTs showed promising efficacy alongside a manageable safety profile.
{"title":"Individualised adjuvant immunotherapy with neoantigen-reactive T cells for gastric signet-ring cell carcinoma","authors":"Naiqing Ding, Qin Liu, Juan Du, Jie Shao, Yang Yang, Ju Yang, Fangjun Chen, Lixia Yu, Baorui Liu, Jia Wei","doi":"10.1002/cti2.1467","DOIUrl":"10.1002/cti2.1467","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objectives</h3>\u0000 \u0000 <p>The signet-ring cell carcinoma (SRCC) of the stomach is highly invasive. Patients with stage III gastric SRCC usually experience tumor recurrence within 2 years after radical surgery. Unfortunately, there is no effective treatment to postpone recurrence following adjuvant chemotherapy. Our study aimed to explore the safety and efficacy of neoantigen-reactive T lymphocytes (NRTs) in patients with stage III gastric SRCC.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>The study included 20 patients with stage III gastric SRCC who received radical surgery and adjuvant chemotherapy. Following the adjuvant chemotherapy, they underwent treatment with a range of one to four cycles of personalised neoantigen-reactive T cells. The primary endpoint was the median progression-free survival (mDFS). The secondary endpoint was safety and immune responses. The median duration of follow-up was 41 months (95% CI: 39–42.9 months).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Our results showed that patients who received adjuvant neoantigen-reactive T-cell immunotherapy demonstrated a propensity towards prolonged disease-free survival (DFS) and overall survival (OS) in comparison to previous studies. The 2-year DFS and OS rates reached 73.7% and 95%, respectively, whereas the 5-year DFS and OS rates were 44% and 69%. The median DFS was 41 months (95% CI: 28.9–53.1 months) and the median OS was not reached. In addition, there was a significant increase in serum concentrations of IL-2, IL-4, IL-6, IL-10, TNF-α and IFN-γ after cell immunotherapy. The adverse reactions were mild.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>In conclusion, adjuvant immunotherapy with NRTs showed promising efficacy alongside a manageable safety profile.</p>\u0000 </section>\u0000 </div>","PeriodicalId":152,"journal":{"name":"Clinical & Translational Immunology","volume":"12 9","pages":""},"PeriodicalIF":5.8,"publicationDate":"2023-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/15/65/CTI2-12-e1467.PMC10494288.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10229893","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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