Current gene therapy最新文献

{"title":"CD1B Expression in Triple-Negative Breast Cancer: Its Implications for Prognosis and Immunotherapy Outcomes.","authors":"Hongwei Jin, Mengting Wan, Shuaikang Pan, Ziqi Wang, Wei Wang, Jinguo Zhang, Xinghua Han","doi":"10.2174/0115665232364481250131071311","DOIUrl":"https://doi.org/10.2174/0115665232364481250131071311","url":null,"abstract":"<p><strong>Introduction: </strong>The absence of the estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) is a hallmark of triple-negative breast cancer (TNBC), which results in fewer treatment options and inferior clinical outcomes. The major histocompatibility complex family includes CD1B. By exposing T cells to lipid antigens, it alters immunological responses. Although the function of CD1B has been investigated in a number of malignancies, its relevance in TNBC has not been fully investigated.</p><p><strong>Method: </strong>In this study, immunohistochemistry (IHC) analysis of tissue samples and public databases was carried out to examine the expression of CD1B and its implications for prognosis in TNBC.</p><p><strong>Result: </strong>Compared to normal tissues, TNBC tissues demonstrated significantly higher levels of CD1B expression. Better overall survival, including survival without distant metastases and survival without recurrence, was found to be associated with higher levels. Additionally, more immune cells, primarily memory B cells and regulatory T cells, entering the TNBC region were found to be associated with greater levels of CD1B. It was found that the immunological microenvironment of TNBC was significantly affected by CD1B. The association between CD1B and immune-related pathways was also identified by examining functional enrichment. Drug sensitivity can be used to identify potential CD1B-targeting therapies. According to these results, CD1B might be a useful prognostic indicator and a possible target for treatment in TNBC.</p><p><strong>Conclusion: </strong>Nevertheless, additional experimental verification is required to verify the clinical significance of CD1B.</p>","PeriodicalId":10798,"journal":{"name":"Current gene therapy","volume":" ","pages":""},"PeriodicalIF":3.8,"publicationDate":"2025-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143398541","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Gene Therapy: Transforming the Battle Against Pancreatic Cancer.","authors":"Rohit Sharma, Sourabh Kumar, Rashmi Ghosh, Kumari Komal, Manish Kumar","doi":"10.2174/0115665232364196250131102330","DOIUrl":"https://doi.org/10.2174/0115665232364196250131102330","url":null,"abstract":"<p><p>Pancreatic cancer remains one of the most aggressive and lethal malignancies, with a dismal prognosis despite advancements in conventional treatment modalities. Gene therapy has emerged as a promising approach to combat pancreatic cancer by targeting the underlying genetic alterations and harnessing the power of the immune system. This review explores the current landscape of gene therapy strategies for pancreatic cancer, including gene replacement therapy, gene silencing, immunotherapy enhancement, and oncolytic virotherapy. Gene replacement therapy aims to restore the function of tumor suppressor genes, such as TP53, while gene silencing targets oncogenes like KRAS (Kirsten rat sarcoma viral oncogene homolog) to inhibit tumor growth. Immunotherapy enhancement, particularly through chimeric antigen receptor (CAR) T-cell therapy, has shown potential in overcoming the immunosuppressive tumor microenvironment. Oncolytic viruses, engineered to replicate in and destroy cancer cells selectively, have demonstrated efficacy in preclinical models and are being evaluated in clinical trials. Recent advances, including the successful treatment of a patient with advanced pancreatic cancer using neoantigen T-cell receptor gene therapy, highlight the potential of personalized gene therapy approaches. However, challenges such as precise gene delivery, tumor heterogeneity, and ethical considerations must be addressed to realize the potential of gene therapy for pancreatic cancer fully. Ongoing research and clinical trials are expected to facilitate the way for the development of safe and effective gene therapies, offering hope for improved outcomes in pancreatic cancer.</p>","PeriodicalId":10798,"journal":{"name":"Current gene therapy","volume":" ","pages":""},"PeriodicalIF":3.8,"publicationDate":"2025-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143398543","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeting Undruggable Proteins: The siRNA Revolution Beyond Small Molecules - Advances, Challenges, and Future Prospects in Therapeutic Innovation.","authors":"Sk Ashif Jan, Abhijit Debnath, Rajesh Kumar Singh, Pankaj Kumar Tyagi, Sachin Singh, Anil Kumar Singh","doi":"10.2174/0115665232357160250123113148","DOIUrl":"https://doi.org/10.2174/0115665232357160250123113148","url":null,"abstract":"<p><p>The field of drug discovery has long been challenged by the existence of \"undruggable\" proteins - targets that have resisted traditional small molecule approaches due to their structural or functional characteristics. This review explores the revolutionary potential of small interfering RNA (siRNA) technology in addressing these elusive targets, marking a paradigm shift in therapeutic development. We discuss the historical development of siRNA technology and its unique mechanism of action, which allows for the silencing of virtually any gene, including those coding for proteins previously deemed undruggable. The review provides a comprehensive analysis of the challenges in targeting undruggable proteins and how siRNA approaches are overcoming these obstacles. We examine several case studies of undruggable targets being successfully addressed by siRNA, including oncogenic proteins like KRAS and c-Myc, transcription factors such as NF-κB and STAT3, and proteins involved in complex protein-protein interactions. The article delves into the latest advances in siRNA design, delivery systems, and targeting strategies, highlighting innovations that enhance specificity and reduce off-target effects. We also discuss the challenges facing siRNA therapeutics, including delivery obstacles, potential immune responses, and regulatory considerations. The review concludes with an exploration of future directions, including combination therapies, personalized medicine approaches, and emerging technologies that complement siRNA strategies. By providing a thorough examination of the advances, challenges, and prospects of using siRNA to target undruggable proteins, this review underscores the transformative potential of this technology in expanding the landscape of therapeutic targets and ushering in a new era of precision medicine.</p>","PeriodicalId":10798,"journal":{"name":"Current gene therapy","volume":" ","pages":""},"PeriodicalIF":3.8,"publicationDate":"2025-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143364224","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Molecular Insights into RNA Modifications and their Role in Shaping Immune Responses and Tumor Microenvironments.","authors":"Ashiq Ali, Tehreem Ajmal, Aisha Khatoon, Kaynaat Akbar, Urooj Irshad, Bilal Murtaza, Ziyi Ji, Abdullah Ali, Qaisar Tanveer, Zhongjing Su","doi":"10.2174/0115665232335322241205063758","DOIUrl":"10.2174/0115665232335322241205063758","url":null,"abstract":"<p><p>RNA modifications play crucial roles in immune system development and function, with dynamic changes essential for diverse cellular processes. Innovative profiling technologies are invaluable for understanding the significance of these modifications in immune cells, both in healthy and diseased states. This review explores the utility of such technologies in uncovering the functions of RNA modifications and their impact on immune responses. Additionally, it delves into the mechanisms through which aberrant RNA modifications influence the tumor microenvironments immune milieu. Despite significant progress, several outstanding research questions remain, highlighting the need for further investigation into the molecular mechanisms underlying RNA modification's effects on immune function in various contexts.</p>","PeriodicalId":10798,"journal":{"name":"Current gene therapy","volume":" ","pages":""},"PeriodicalIF":3.8,"publicationDate":"2025-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143022506","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Exploring Genetic and Receptor-Based Dopaminergic Strategies for Antidepressant Drug Development.","authors":"Arzoo Pannu, Ramesh K Goyal","doi":"10.2174/0115665232334693250110175517","DOIUrl":"https://doi.org/10.2174/0115665232334693250110175517","url":null,"abstract":"<p><p>The dopamine (DA) system is central to mood regulation, motivation, and reward processing, making it a critical focus for understanding Major Depressive Disorder (MDD). While the dopaminergic system's role in MDD pathophysiology has been acknowledged, gaps remain in linking specific receptor subtypes and genetic factors to depression-like phenotypes. This study explores the interplay between dopamine receptor subtypes (D1-D5) and associated genetic variations, particularly focusing on receptor heterodimers and polymorphisms influencing dopamine biosynthesis, signalling, and metabolism. A comprehensive review of molecular mechanisms highlights key findings: alterations in D1-D2 heterodimers contribute to mood dysregulation; D3 receptor downregulation correlates with depressive behaviour; and genetic polymorphisms, including those in tyrosine hydroxylase and dopamine transporter (DAT) genes, influence dopamine levels and receptor functions. Emerging data from neuroimaging and animal models confirm the pivotal role of dopamine receptor subtypes in MDD, offering insights into their therapeutic targeting. Here, we show that dopaminergic dysfunction underpins MDD's pathophysiology, with receptor-specific mechanisms presenting novel drug targets. Understanding these pathways facilitates precision medicine approaches, bridging the gap between genetic predisposition and receptor pharmacology, and paving the way for tailored antidepressant strategies with improved efficacy and reduced side effects.</p>","PeriodicalId":10798,"journal":{"name":"Current gene therapy","volume":" ","pages":""},"PeriodicalIF":3.8,"publicationDate":"2025-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143022505","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Plasmalogens Activate AKT/mTOR Signaling to Attenuate Reactive Oxygen Species Production in Spinal Cord Injury.","authors":"Mengdan Cheng, Yan Gao, Yiqing Wu, Liangliang Zhang, Bai Xu, Xiaojie Lu","doi":"10.2174/0115665232330349241225074627","DOIUrl":"https://doi.org/10.2174/0115665232330349241225074627","url":null,"abstract":"<p><strong>Background: </strong>Plasmalogens, the primary phospholipids in the brain, possess intrinsic antioxidant properties and are crucial components of the myelin sheath surrounding neuronal axons. While their neuroprotective effects have been demonstrated in Alzheimer's disease, their potential benefits in spinal cord injury remain unexplored. This study investigates the reparative effects of plasmalogens on spinal cord injury and the underlying mechanisms.</p><p><strong>Methods: </strong>In vitro, we developed dorsal root ganglion (DRG) and RAW 264.7 cell models under high-reactive oxygen species (ROS) conditions to assess ROS levels, neuronal damage, and inflammatory microenvironment changes before and after plasmalogen application. In vivo, we used a complete mouse spinal cord transection model to evaluate changes in ROS levels, neuronal demyelination, and apoptosis following plasmalogen treatment. Additionally, we assessed sensory and motor function recovery and investigated the regulatory effects of plasmalogens on the AKT/mTOR signaling pathway.</p><p><strong>Results: </strong>In high-ROS cell models, plasmalogens protected DRG neurons (TUJ-1) from axonal damage and modulated the proinflammatory/anti-inflammatory balance in RAW 264.7 cells. In vivo, plasmalogens significantly reduced ROS levels, improved the immune microenvironment, decreased the proinflammatory (iNOS)/anti-inflammatory (ARG-1) ratio, lowered neuronal (TUJ-1) apoptosis (Caspase-3, BAX), and reduced axonal degeneration while promoting myelin (MBP) regeneration, indicating a neuroprotective effect. These findings are linked to the activation of the AKT/mTOR signaling pathway.</p><p><strong>Conclusion: </strong>Plasmalogens reduce ROS levels and regulate inflammation-induced damage, contributing to neuroprotection. This study reveals that plasmalogens promote remyelination, reduce axonal degeneration and neuronal apoptosis, and-used here for the first time in spinal cord injury repair- may protect neurons by reducing ROS levels and activating the AKT/mTOR signaling pathway.</p>","PeriodicalId":10798,"journal":{"name":"Current gene therapy","volume":" ","pages":""},"PeriodicalIF":3.8,"publicationDate":"2025-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143001542","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"siRNA Knocking Down in HepG2 Cells Identifies PFKFB4 and HNF4α as Key Genes Important for Cancer Cell Survival.","authors":"Amer Imraish, Walhan Alshaer, Tuqa Abu-Thiab, Fatima Enaya, Hamzeh J Al-Ameer, Afnan Al-Hunaiti, Mohammad Abumurad, Malek Zihlif","doi":"10.2174/0115665232337735250101121115","DOIUrl":"https://doi.org/10.2174/0115665232337735250101121115","url":null,"abstract":"<p><strong>Introduction: </strong>Liposomes are versatile delivery systems for encapsulating small interfering RNAs (siRNAs) because they enhance cellular uptake and gene silencing. This study compares the new liposome formula to commercial lipofectamine in delivering siRNAs targeting hepatic carcinoma genes, focusing on HNF4-α and PFKFB4.</p><p><strong>Methods: </strong>Flow cytometry and confocal microscopy revealed efficient internalization of PE-Rhod- B labeled lipoplexes in HepG2 cells, while cytotoxicity assays demonstrated significant reductions in cell viability, particularly with siHNF4-α and siPFKFB4.</p><p><strong>Results: </strong>The newly formulated liposomes showed superior efficacy, achieving nearly 93% cytotoxicity at 100 nM, compared to just 50% with lipofectamine at the same concentration. Furthermore, real-time PCR confirmed that the liposome-encapsulated siHNF4-α reduced HNF4-α mRNA expression by tenfold at 100 nM, compared to a twofold reduction with lipofectamine at 200 nM. Similarly, siPFKFB4 delivered via liposomes showed a dose-dependent 35-fold reduction in PFKFB4 mRNA expression at 100 nM, outperforming the maximum reduction achieved by lipofectamine. The IC50 values for all siRNA treatment groups were significantly lower when using the liposome formula, reflecting improved delivery efficiency.</p><p><strong>Conclusion: </strong>These results demonstrate the potential of liposome formulations for therapeutic siRNA delivery. The encapsulation enhances cellular uptake and gene silencing efficiency, making the liposome formula a promising candidate for targeted gene therapy in hepatic carcinoma. Further research should explore it's in vivo biodistribution and potential combination therapies.</p>","PeriodicalId":10798,"journal":{"name":"Current gene therapy","volume":" ","pages":""},"PeriodicalIF":3.8,"publicationDate":"2025-01-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143001544","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Development of Lentiviral Packaging Cells and Scale Up of Production to Meet the Growing Demand in Cell and Gene Therapy.","authors":"Yasemin van Heuvel, Jörn Stitz","doi":"10.2174/0115665232332412241118063211","DOIUrl":"https://doi.org/10.2174/0115665232332412241118063211","url":null,"abstract":"<p><p>Gamma-Retroviral (RVVs) and lentiviral vectors (LVVs) represent indispensable tools in somatic gene therapy, mediating the efficient, stable transfer of therapeutic genes into a variety of human target cells. LVVs, in contrast to RVVs, are capable of stably genetically modifying non-proliferating target cells, making them the superior instrument in cell and gene therapy. To date, the LVV manufacturing process employs human embryonic kidney cells (HEK293) and derivatives thereof transiently transfected with multiple plasmids encoding the required viral vector components. Alternatively, stable packaging cell lines were developed and engineered to express all vector components in trans. Currently, these cells are mostly cultured in cell stacks, where they grow adherently in 2D layers, limiting the scale-up of vector production. The production of viral vectors using stable suspension cell lines enables larger-scale production and higher yields under controlled conditions. Here, we review the improvements made to enhance vector safety and production yield. Current advancements in the establishment of stable packaging cell lines enabling inducible and constitutive LVV production are summarized and discussed. Manufacturing processes for lentiviral vectors using bioreactors with perfusion systems are required to meet the growing demand in cell and gene therapy and to reduce production and therapy costs.</p>","PeriodicalId":10798,"journal":{"name":"Current gene therapy","volume":" ","pages":""},"PeriodicalIF":3.8,"publicationDate":"2025-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142982988","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"O-substituted Tertiary Amine-chitosans as Promising Nanocarriers for siRNA Delivery.","authors":"André Miguel Martinez Júnior, Vera Aparecida de Oliveira, Marcio José Tiera","doi":"10.2174/0115665232335957241122164034","DOIUrl":"https://doi.org/10.2174/0115665232335957241122164034","url":null,"abstract":"<p><strong>Introduction: </strong>The clinical translation of chitosan-based formulations for siRNA delivery has been partially limited by their poor stability/solubility at physiological conditions, although they have good biocompatibility and cost-effectiveness.</p><p><strong>Method: </strong>In this study, the chitosan was O-substituted with diisopropylethylamine (DIPEA) groups, which improved its solubility at pH 7.4 by increasing the degree of ionization and enhanced the ability of chitosan to load siRNA at very low amine/phosphate (N/P) ratios. The O-DIPEAchitosan/ siRNA nanopolyplexes were self-assembled by complexation and presented positive Zeta potentials (ζ = +8 to +10 mV), spherical-like morphology, 200-300 nm size, low polydispersity index (PDI < 0.2), and were able to protect the siRNA from degradation by RNAse. Also, the resistance to albumin-induced disassembly and aggregation revealed both good structural and colloidal stabilities of the siRNA nanopolyplexes.</p><p><strong>Result: </strong>The nanopolyplexes displayed low cytotoxicities in RAW 264.7 macrophages and were successfully uptaken by both macrophages and HeLa cells achieving internalization efficiency similar to Lipofectamine. A positive correlation was observed between the physicochemical properties of the siRNA nanocarrier and its transfection efficiency.</p><p><strong>Conclusion: </strong>A knockdown of about 60-70% of tumor necrosis factor alpha (TNFα) was reached in lipopolysaccharide-stimulated macrophages treated with O-DIPEA-chitosan/siTNFα nanopolyplexes. Overall, the results confirmed that O-DIPEA chitosans are promising carriers for siRNA delivery.</p>","PeriodicalId":10798,"journal":{"name":"Current gene therapy","volume":" ","pages":""},"PeriodicalIF":3.8,"publicationDate":"2025-01-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142983000","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Implications of EBV-Encoded and EBV-Related miRNAs in Tumors.","authors":"Prankur Awasthi, Arjun Singh Kohli, Manish Dwivedi, Saba Hasan","doi":"10.2174/0115665232327174241211075019","DOIUrl":"https://doi.org/10.2174/0115665232327174241211075019","url":null,"abstract":"<p><p>Over 90% of people are infected with the human g-herpesvirus known as the Epstein- Barr virus (EBV). Cancers, such as gastric carcinoma, non-Hodgkin's lymphoma, nasopharyngeal carcinoma, Hodgkin's lymphoma, and Burkitt lymphoma, are thought to be linked with EBV. It is noteworthy that the first virus discovered that encodes microRNAs (miRNAs) was EBV, and these miRNAs show expression at the different phases of EBV infection. There is growing evidence that EBV-encoded miRNAs influence the growth of EBV-associated tumors. These EBV miRNAs, i.e., BamHI-H rightward fragment 1-derived microRNAs (BHRF1miRNA) and BamHI-A rightward fragment-derived microRNAs (BART miRNAs), are crucial for the persistence of viral infection and the avoidance of host defenses. Currently, significant advancements have been made in analyzing the microRNAs that are found in the duration of EBV infection, in vitro studies identified molecular targets of miRNAs and in vivo studies enhanced our understanding regarding the pathophysiology of these molecules. An extensive look into the pro-carcinogenic impact of microRNAs associated with EBV will increase our understanding of the molecular mechanisms of EBV-associated tumors. In this paper, we have highlighted the functions of miRNAs in EBV infection as well as recent developments in miRNA-based therapeutic and diagnostic approaches that could be useful for EBV-related malignancies. Significantly, targeted therapies against EBV miRNAs are advancing rapidly, with emerging approaches such as miRNA sponges, anti-miRNA oligonucleotides, and CRISPR/Cas9 technologies. These innovations indicate the imminent onset of a new era in the treatment of EBV-associated tumors.</p>","PeriodicalId":10798,"journal":{"name":"Current gene therapy","volume":" ","pages":""},"PeriodicalIF":3.8,"publicationDate":"2025-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142946277","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}