Immunotherapy advances最新文献

{"title":"Lung immune challenge study protocol: controlled exposure to inhaled resiquimod (R848) to study mechanisms of inflammation.","authors":"Akhilesh Jha, Marie Fisk, Jamie Forrester, Jacqui Galloway, Jade Joseph, Robyn Staples, Karl P Sylvester","doi":"10.1093/immadv/ltaf005","DOIUrl":"10.1093/immadv/ltaf005","url":null,"abstract":"<p><p>This study aims to develop a human lung immune challenge model using inhaled Resiquimod (R848), a Toll-like receptor 7/8 agonist, to investigate inflammatory mechanisms involved in the human respiratory mucosa in health and disease. This approach seeks to induce innate immune anti-viral responses in the lungs and blood, with a suitable dose of inhaled R848 that is clinically tolerable. The study will include healthy volunteers and individuals with asthma. The primary outcome is a change in CXCL10, a biomarker representative of anti-viral responses, at 24 hours post-exposure. Secondary outcomes include changes in lung function, physiological parameters, and inflammatory markers, including C-reactive protein and eosinophil counts. This trial involves a single ascending dose, randomized, single-blind, placebo-controlled design. Participants will receive R848 via nebulization in escalating doses from 0.1 to 100 µg/ml or saline placebo. Safety assessments include spirometry, vital signs, and blood samples to monitor systemic and lung-specific immune responses. The study will contribute to understanding immune pathways in asthma and provide a platform for testing novel anti-inflammatory therapeutics. The protocol has been approved by relevant ethics committees and will be disseminated via peer-reviewed publications and open-access data repositories.</p>","PeriodicalId":73353,"journal":{"name":"Immunotherapy advances","volume":"5 1","pages":"ltaf005"},"PeriodicalIF":4.1,"publicationDate":"2025-02-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11976720/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143812981","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Human challenge models for vaccine development-strengths, limitations, and expansion into endemic settings: a HIC-Vac meeting report.","authors":"Helen R Wagstaffe, Stephanie Ascough, Peter J M Openshaw","doi":"10.1093/immadv/ltaf004","DOIUrl":"https://doi.org/10.1093/immadv/ltaf004","url":null,"abstract":"<p><p>The HIC-Vac network is a unique association of researchers focussed on the development and use of human infection challenge (HIC, otherwise known as controlled human infection models or CHIM) studies for vaccine and therapeutic development, particularly for pathogens of high global impact. The fifth annual meeting of the HIC-Vac network was held on 1-3 November 2023. The theme of the meeting was capacity-building in endemic settings particularly in low- and middle-income countries (LMIC), where pathogens cause the greatest morbidity and mortality. In this report we highlight the strengths and limitations of HIC and expansion of such studies into endemic settings, noting that immune responses and vaccine efficacy differ across diverse settings and populations. The consensus was that HIC studies must not be restricted to high income settings if they are to be relevant to LMIC populations. This report summarizes the work presented at the HIC-Vac annual meeting, highlighting current and future challenge models, challenge agent manufacture, public engagement, ethics, and industry perspectives.</p>","PeriodicalId":73353,"journal":{"name":"Immunotherapy advances","volume":"5 1","pages":"ltaf004"},"PeriodicalIF":4.1,"publicationDate":"2025-02-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12012439/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144013922","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Imaging antigen processing and presentation in cancer.","authors":"Doreen Lau, Tim Elliott","doi":"10.1093/immadv/ltaf002","DOIUrl":"https://doi.org/10.1093/immadv/ltaf002","url":null,"abstract":"<p><strong>Introduction: </strong>Antigen processing and presentation are vital processes of the adaptive immunity. These processes involve a series of intracellular and extracellular events, including the enzymology within cells during antigen processing, the loading and presentation of antigenic peptides on major histocompatibility complexes, the recruitment of T cells, their interaction with antigen-presenting cells, and the expression of adhesion, co-stimulatory and co-inhibitory molecules at the T cell immunological synapse. These events collectively fine-tune and sustain antigen recognition and T cell function. Dysregulation of this machinery can profoundly impact the efficacy of cancer immunotherapy. Imaging technologies have emerged as powerful tools for elucidating the mechanisms underlying antigen processing and presentation. By providing complementary perspectives into the cellular and molecular interactions at play, imaging has significantly enhanced our understanding of these complex immunological events in cancer. Such insights can improve the monitoring of immunotherapy responses, facilitate the identification of effective treatments, and aid in predicting patient outcomes.</p><p><strong>Methods: </strong>This review explores the role of imaging in studying antigen processing and presentation in the context of cancer.</p><p><strong>Conclusion: </strong>It highlights key considerations for developing imaging tools and biomarkers to detect components of these pathways. Additionally, it examines the strengths and limitations of various imaging approaches and discusses their potential for clinical translation.</p>","PeriodicalId":73353,"journal":{"name":"Immunotherapy advances","volume":"5 1","pages":"ltaf002"},"PeriodicalIF":4.1,"publicationDate":"2025-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12012451/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144059204","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Bispecific T-cell engagers for the recruitment of T cells in solid tumors: a literature review.","authors":"Laura Dewaele, Ricardo A Fernandes","doi":"10.1093/immadv/ltae005","DOIUrl":"10.1093/immadv/ltae005","url":null,"abstract":"<p><p>In the past decade, T-cell-based immunotherapies have grown to become some of the most promising treatments for cancer. Following the success of immune checkpoint inhibitors, other T-cell-based therapies emerged including CAR-T cells and bispecific T-cell engagers (BiTEs). BiTEs have the unique ability to crosslink T cells and tumor cells independently of major histocompatibility complex (MHC) restriction. They do not rely on TCR specificity or the CD4+/CD8+ costimulatory molecules, overcoming tumor MHC downregulation and low-affinity TCR binding. However, like many other immunotherapies, BiTEs have shown limited success beyond the treatment of hematological malignancies. BiTEs for the treatment of solid tumors still face challenges. Studies in gastrointestinal tumors have revealed Fc toxicity, short half-lives, and immunotoxicity, leading to Fc-silenced half-life extended BiTEs with humanized single-chain variable fragments. Studies in prostate tumors, lung tumors, and malignant gliomas have identified promising targets in PSMA, DLL3, and EGFRvIII, respectively, but also highlighted the problems of on-target off-tumor and BiTE-specific toxicities and inaccessible or immunosuppressive tumor microenvironments. Ongoing research to overcome these limitations remains an interesting field to follow, as BiTEs have the potential to be a powerful tool, especially when used in combination with other immunotherapies.</p>","PeriodicalId":73353,"journal":{"name":"Immunotherapy advances","volume":"5 1","pages":"ltae005"},"PeriodicalIF":4.1,"publicationDate":"2025-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11904783/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143625819","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Delivery of IL-12 by neoantigen-reactive T cells promotes antitumor immunity in murine osteosarcoma mode.","authors":"Cong Tian, Xingxing Sun, Hongling Zhu, Meixiang Zhou, Qingyu Chen, Daliu Min, Yan Huang, Kun Han","doi":"10.1093/immadv/ltae010","DOIUrl":"10.1093/immadv/ltae010","url":null,"abstract":"<p><strong>Purpose: </strong>Despite the proven clinical benefits of cytokine therapy in cancer treatment, systemic administration of cytokines such as IL-12 is constrained by dose-limiting toxicities and short half-lives. To address these challenges, we explored a localized cytokine delivery strategy using engineered neoantigen-reactive T (NRT) cells as carriers in a murine model of osteosarcoma.</p><p><strong>Materials and methods: </strong>We used a neoantigen from K7M2 osteosarcoma cells to retrovirally transduce NRT cells to express an inducible form of IL-12. We evaluated the engineered NRT cells' antitumor activity and the production of IL-12 and IFN-γ upon in vitro co-culture with tumor cells. We systemically administered NRT-IL-12 cells in a mouse model of osteosarcoma to assess their impact on tumor growth and survival.</p><p><strong>Results: </strong><i>In vitro</i> assays demonstrated that the engineered NRT cells exhibited enhanced antitumor activity and produced elevated levels of IL-12 and IFN-γ. In the mouse model of osteosarcoma, systemic administration of NRT-IL-12 cells resulted in a significant reduction in tumor growth and an increase in survival rates compared to the administration of control NRT cells. Further analysis revealed that NRT-IL-12 cells induced a profound increase in CD8+ T-cell infiltration and a decrease in Treg cells within the tumor microenvironment.</p><p><strong>Conclusion: </strong>Our study presents a novel and efficacious strategy for osteosarcoma immunotherapy by harnessing NRT cells as targeted cytokine delivery vehicles.</p>","PeriodicalId":73353,"journal":{"name":"Immunotherapy advances","volume":"5 1","pages":"ltae010"},"PeriodicalIF":4.1,"publicationDate":"2024-11-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11684073/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142916439","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Systematic review and meta-analysis of COVID-19 mRNA vaccine effectiveness against hospitalizations in adults.","authors":"Bill Kang-Fai Wong, Neil A Mabbott","doi":"10.1093/immadv/ltae011","DOIUrl":"10.1093/immadv/ltae011","url":null,"abstract":"<p><strong>Background: </strong>During the coronavirus disease 2019 (COVID-19) pandemic, Pfizer/BioNTech BNT162b2, and Moderna mRNA-1273 vaccines were central to the global pandemic control measures.</p><p><strong>Methods: </strong>Here, we conducted a systematic review and meta-analysis to evaluate their real-world vaccine effectiveness (VE). Our study focussed on those that reported the efficacy of these vaccines against COVID-19 hospitalization. Hospitalization was chosen as the primary outcome as it directly reflects the ability of the vaccine to prevent severe disease. A literature search was undertaken using Medline and Embase on 25 February 2024. From this, 50 studies out of 18,347 articles were included for further analysis.</p><p><strong>Results: </strong>High VE against hospitalization was reported for both the BNT162b2 and mRNA-1273 COVID-19 vaccines when used either as a primary vaccination series (2-dose) or following an additional booster dose (3-dose). Meta-analysis indicated that the pooled VE estimates for each of these vaccination protocols ranged from 84% to 86%, suggesting strong protectiveness. Our data also imply that booster doses can restore waning effectiveness, with no significant differences observed in VE between the 2-dose and 3-dose protocols. However, subgroup analysis revealed an association between the presence of the Omicron variant and a drop in VE, indicating that future emerging SARS-CoV-2 virus variants could similarly affect VE.</p><p><strong>Conclusions: </strong>Our review underscores the importance of ongoing research to ensure vaccine strategies remain effective against evolving variants. Our study also identified the need for expanding data collection to include underrepresented populations.</p>","PeriodicalId":73353,"journal":{"name":"Immunotherapy advances","volume":"4 1","pages":"ltae011"},"PeriodicalIF":4.1,"publicationDate":"2024-11-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11655844/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142866373","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Hyperactivation of the PI3K pathway in inborn errors of immunity: current understanding and therapeutic perspectives.","authors":"Hanna IJspeert, Virgil A S H Dalm, Menno C van Zelm, Emily S J Edwards","doi":"10.1093/immadv/ltae009","DOIUrl":"10.1093/immadv/ltae009","url":null,"abstract":"<p><p>The phosphoinositide-3-kinase (PI3K) pathway function is crucial to the normal development, differentiation, and function of immune cells including B, T, and NK cells. Following the description of two cohorts of patients with an inboirn error of immunity (also known as primary immunodeficiency) with gain-of-function variants in the <i>PIK3CD</i> gene a decade ago, the disease entity activated PI3K delta syndrome (APDS) was named. Since then, many more patients with <i>PIK3CD</i> variants have been described, and loss-of-function variants in <i>PIK3R1</i> and <i>PTEN</i> have also been linked to APDS. Importantly, the availability of small molecules that inhibit the PI3K pathway has enabled targeted treatment of APDS patients. In this review, we define (i) the PI3K pathway and its role in inborn errors of immunity; (ii) the clinical and immunological presentation of APDS1 (<i>PIK3CD</i> GOF), APDS2 (<i>PIK3R1</i> LOF), and related disorders; (iii) Diagnostic approaches to identify and functionally validate the genetic causes of disease; (iv) therapeutic interventions to target PI3K hyperactivation; and finally (v) current challenges and future perspectives that require attention for the optimal treatment of patients with APDS and APDS-L diseases.</p>","PeriodicalId":73353,"journal":{"name":"Immunotherapy advances","volume":"4 1","pages":"ltae009"},"PeriodicalIF":4.1,"publicationDate":"2024-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11638974/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142831011","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"High-affinity T cell receptor ImmTAC® bispecific efficiently redirects T cells to kill tumor cells expressing the cancer-testis antigen PRAME.","authors":"Ana R Ribeiro, Camille Britton-Rivet, Laura Collins, Ricardo J Carreira, Sylvie Moureau, Adel Benlahrech, Sarah Stanhope, Stephen Harper, Nathaniel Liddy, Tara M Mahon, Kristina Petrovic, Mark Fife, David Depoil, Philip Addis, Nicole Bedke, Lucie Bouard, Ronan O'Dwyer, Duncan Gascoyne, Koustubh Ranade","doi":"10.1093/immadv/ltae008","DOIUrl":"10.1093/immadv/ltae008","url":null,"abstract":"<p><strong>Background: </strong>PRAME (<i>Pr</i>eferentially expressed <i>A</i>ntigen in <i>Me</i>lanoma) is a cancer-testis antigen expressed in several tumor indications, representing an attractive anticancer target. However, its intracellular location limits targeting by traditional methods. PRAME peptides are presented on the surface of tumor cells by human leukocyte antigen (HLA) molecules, indicating that a T cell receptor (TCR)-based strategy that redirects T cells to kill PRAME⁺ tumors could be a novel immunotherapeutic option. We confirm that PRAME protein is expressed in cutaneous melanoma, including rare subtypes with limited treatment options, as well as primary and metastatic lung, breast, endometrial, and ovarian tumors. Furthermore, PRAME is expressed homogeneously across tumors with distinct oncogenic mutations, mutation burden, PD-L1 expression, immune infiltration, and features of immune checkpoint resistance. Immunopeptidomic analysis of primary tumors detected HLA class I-restricted PRAME peptides.</p><p><strong>Methods: </strong>A TCR recognizing PRAME peptide SLLQHLIGL was engineered to high affinity and fused to a CD3 engaging domain to create a TCRxCD3 bispecific molecule (<i>I</i>mmune-<i>m</i>obilizing <i>m</i>onoclonal TCR <i>A</i>gainst <i>C</i>ancer, ImmTAC®) with the ability to redirect polyclonal T cells to efficiently kill PRAME⁺ cells.</p><p><strong>Rs: </strong>The degree of T cell activation was positively correlated with peptide-HLA abundance, with as few as 10 epitopes per cell sufficient for target cell killing. Impaired ImmTAC®-redirected cytotoxicity of exhausted T cells was rescued using an anti-PD-1 antibody, supporting the use of a combination strategy to treat tumors with active PDL1-PD1 axes.</p><p><strong>Conclusions: </strong>Our data demonstrate selective and efficient T cell activation and killing by a PRAME-directed TCRxCD3 bispecific, supporting further investigation in multiple cancer indications.</p>","PeriodicalId":73353,"journal":{"name":"Immunotherapy advances","volume":"4 1","pages":"ltae008"},"PeriodicalIF":4.1,"publicationDate":"2024-11-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11631188/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142808543","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A rapid method to assess the <i>in vivo</i> multi-functionality of adoptively transferred engineered TCR T cells.","authors":"Anthony T Tan, Shou Kit Hang, Nicole Tan, Thinesh L Krishnamoorthy, Wan Cheng Chow, Regina Wanju Wong, Lu-En Wai, Antonio Bertoletti","doi":"10.1093/immadv/ltae007","DOIUrl":"10.1093/immadv/ltae007","url":null,"abstract":"<p><strong>Introduction: </strong>The clinical efficacy of chimeric antigen and T cell receptor (TCR) T cell immunotherapies is attributed to their ability to proliferate and persist <i>in vivo</i>. Since the interaction of the engineered T cells with the targeted tumour or its environment might suppress their function, their functionality should be characterized not only before but also after adoptive transfer.</p><p><strong>Materials and methods: </strong>We sought to achieve this by adapting a recently developed Severe acute respiratory syndrome <i>coronavirus 2</i> (SARS-CoV-2) rapid whole blood T cell assay to stimulate engineered TCR T cells in small volumes of whole blood (<1 ml) without <i>in vitro</i> cellular purification. As a proof-of-concept, we used this method to longitudinally study two patients with primary Hepatitis B Virus (HBV)-related hepatocellular carcinoma who received multiple dose-escalating infusions of transiently functional mRNA-engineered HBV-TCR T cells.</p><p><strong>Results: </strong>We demonstrated that a simple pulsing of whole blood with a peptide corresponding to the epitope recognized by the specific HBV-TCR elicited Th1 cytokine secretion in both patients only after HBV-TCR T cell treatment and not before. The amount of cytokines secreted also showed an infusion-dose-dependent association.</p><p><strong>Discussions: </strong>These findings support the utility of the whole blood cytokine release assay in monitoring the <i>in vivo</i> function and quantity of engineered T cell products following adoptive transfer.</p>","PeriodicalId":73353,"journal":{"name":"Immunotherapy advances","volume":"4 1","pages":"ltae007"},"PeriodicalIF":4.1,"publicationDate":"2024-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11452736/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142383327","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Advancements in nuclear imaging using radiolabeled nanobody tracers to support cancer immunotherapy.","authors":"Katty Zeven, Yoline Lauwers, Lynn De Mey, Jens M Debacker, Tessa De Pauw, Timo W M De Groof, Nick Devoogdt","doi":"10.1093/immadv/ltae006","DOIUrl":"https://doi.org/10.1093/immadv/ltae006","url":null,"abstract":"<p><p>The evolving landscape of cancer immunotherapy has revolutionized cancer treatment. However, the dynamic tumor microenvironment has led to variable clinical outcomes, indicating a need for predictive biomarkers. Noninvasive nuclear imaging, using radiolabeled modalities, has aided in patient selection and monitoring of their treatment response. This approach holds promise for improving diagnostic accuracy, providing a more personalized treatment regimen, and enhancing the clinical response. Nanobodies or single-domain antibodies, derived from camelid heavy-chain antibodies, allow early timepoint detection of targets with high target-to-background ratios. To date, a plethora of nanobodies have been developed for nuclear imaging of tumor-specific antigens, immune checkpoints, and immune cells, both at a preclinical and clinical level. This review comprehensively outlines the recent advancements in nanobody-based nuclear imaging, both on preclinical and clinical levels. Additionally, the impact and expected future advancements on the use of nanobody-based radiopharmaceuticals in supporting cancer diagnosis and treatment follow-up are discussed.</p>","PeriodicalId":73353,"journal":{"name":"Immunotherapy advances","volume":"4 1","pages":"ltae006"},"PeriodicalIF":4.1,"publicationDate":"2024-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11402390/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142302600","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}