Molecular TherapyPub Date : 2025-01-25DOI: 10.1016/j.ymthe.2025.01.035
Malak Khalifeh, Huda Salman
{"title":"Engineering resilient CAR T cells for immunosuppressive environment.","authors":"Malak Khalifeh, Huda Salman","doi":"10.1016/j.ymthe.2025.01.035","DOIUrl":"10.1016/j.ymthe.2025.01.035","url":null,"abstract":"<p><p>Chimeric antigen receptor (CAR) T cell therapy has revolutionized cancer treatment and is now being explored for other diseases, such as autoimmune disorders. While the tumor microenvironment (TME) in cancer is often immunosuppressive, in autoimmune diseases, the environment is typically inflammatory. Both environments can negatively impact CAR T cell survival: the former through direct suppression, hypoxia, and nutrient deprivation, and the latter through chronic T cell receptor (TCR) engagement, risking exhaustion. Mechanisms of resistance include T cell exhaustion, dysfunction, and the impact of the TME. Chronic antigenic stimulation leads to CAR T cell exhaustion. CAR construct design, including co-stimulatory domains, hinge, transmembrane regions, promoters, the affinity of the binder site, and on/off rate plays a crucial role in modulating CAR T cell function and resistance. This review discusses the impact of the in vitro development of CAR T cells, albeit in relation to the TME, on therapeutic outcomes. The use of alternative cell sources, multi-antigen targeting, and reengineering the TME, are discussed. The review emphasizes the need for continued innovation in CAR T cell design and manufacturing to optimize therapeutic efficacy and durability, especially in the face of varying environmental challenges.</p>","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":" ","pages":""},"PeriodicalIF":12.1,"publicationDate":"2025-01-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143040258","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Molecular TherapyPub Date : 2025-01-25DOI: 10.1016/j.ymthe.2025.01.037
Bingxin Liu, Yamato Sajiki, Nicole Littlefield, Yongan Hu, William D Stuart, Anusha Sridharan, Xuemei Cui, Matthew E Siefert, Koichi Araki, Assem G Ziady, Donglu Shi, Jeffery A Whitsett, Yutaka Maeda
{"title":"PBAE-PEG-based lipid nanoparticles for lung cell-specific gene delivery.","authors":"Bingxin Liu, Yamato Sajiki, Nicole Littlefield, Yongan Hu, William D Stuart, Anusha Sridharan, Xuemei Cui, Matthew E Siefert, Koichi Araki, Assem G Ziady, Donglu Shi, Jeffery A Whitsett, Yutaka Maeda","doi":"10.1016/j.ymthe.2025.01.037","DOIUrl":"10.1016/j.ymthe.2025.01.037","url":null,"abstract":"<p><p>Exemplified by successful use in COVID-19 vaccination, delivery of modified mRNA encapsulated in lipid nanoparticles (LNPs) provides a framework for treating various genetic and acquired disorders. However, LNPs that can deliver mRNA into specific lung cell types have not yet been established. Here, we sought to determine whether poly(β-amino ester)s (PBAE) or PEGylated PBAE (PBAE-PEG) in combination with 4A3-SC8/DOPE/cholesterol/DOTAP LNPs could deliver mRNA into different types of lung cells in vivo. PBAE-PEG/LNP was similar to Lipofectamine MessengerMAX followed by PBAE/LNP for mRNA transfection efficiency in HEK293T cells in vitro. PBAE-PEG/LNP administered by intravenous (IV) injection achieved 73% mRNA transfection efficiency into lung endothelial cells, while PBAE-PEG/LNP administered by intratracheal (IT) injection achieved 55% efficiency in lung alveolar type II (ATII) epithelial cells in mice in vivo. PBAE/LNP administered by IT injection were superior for specific delivery into lung airway club epithelial cells compared to PBAE-PEG/LNP. Lipofectamine MessengerMAX was inactive in vivo. 5-Methoxyuridine-modified mRNA was more efficient than unmodified mRNA in vivo but not in vitro. Our findings indicate that PBAE-PEG/LNP and PBAE/LNP can transfect multiple lung cell types in vivo, which can be applied in gene therapy targeting genetic lung diseases.</p>","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":" ","pages":""},"PeriodicalIF":12.1,"publicationDate":"2025-01-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143046992","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Molecular TherapyPub Date : 2025-01-25DOI: 10.1016/j.ymthe.2025.01.041
Christopher J Walkey, Kathy J Snow, Jote Bulcha, Aaron R Cox, Alexa E Martinez, M Cecilia Ljungberg, Denise G Lanza, Marco De Giorgi, Marcel A Chuecos, Michele Alves-Bezerra, Carlos Flores Suarez, Sean M Hartig, Susan G Hilsenbeck, Chih-Wei Hsu, Ethan Saville, Yaned Gaitan, Jeff Duryea, Seth Hannigan, Mary E Dickinson, Oleg Mirochnitchenko, Dan Wang, Cathleen M Lutz, Jason D Heaney, Guangping Gao, Stephen A Murray, William R Lagor
{"title":"A comprehensive atlas of AAV tropism in the mouse.","authors":"Christopher J Walkey, Kathy J Snow, Jote Bulcha, Aaron R Cox, Alexa E Martinez, M Cecilia Ljungberg, Denise G Lanza, Marco De Giorgi, Marcel A Chuecos, Michele Alves-Bezerra, Carlos Flores Suarez, Sean M Hartig, Susan G Hilsenbeck, Chih-Wei Hsu, Ethan Saville, Yaned Gaitan, Jeff Duryea, Seth Hannigan, Mary E Dickinson, Oleg Mirochnitchenko, Dan Wang, Cathleen M Lutz, Jason D Heaney, Guangping Gao, Stephen A Murray, William R Lagor","doi":"10.1016/j.ymthe.2025.01.041","DOIUrl":"10.1016/j.ymthe.2025.01.041","url":null,"abstract":"<p><p>Gene therapy with adeno-associated virus (AAV) vectors requires knowledge of their tropism within the body. Here we analyze the tropism of 10 naturally occurring AAV serotypes (AAV3B, AAV4, AAV5, AAV6, AAV7, AAV8, AAV9, AAVrh8, AAVrh10, and AAVrh74) following systemic delivery into male and female mice. A transgene-expressing ZsGreen and Cre recombinase was used to identify transduction in a cell-dependent manner based on fluorescence. Cre-driven activation of tdTomato fluorescence offered superior sensitivity for transduced cells. All serotypes except AAV3B and AAV4 had high liver tropism. Fluorescence activation revealed transduction of unexpected tissues, including adrenals, testes, and ovaries. Rare transduced cells within tissues were also readily visualized. Biodistribution of AAV genomes correlated with fluorescence, except in immune tissues. AAV4 was found to have a pan-endothelial tropism while also targeting pancreatic beta cells. This public resource enables selection of the best AAV serotypes for basic science and preclinical applications in mice.</p>","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":" ","pages":""},"PeriodicalIF":12.1,"publicationDate":"2025-01-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143040245","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"TRAF1 promotes osteoclastogenesis by enhancing metabolic adaptation to oxidative phosphorylation in an AKT-dependent manner.","authors":"Honglei Kang, Renpeng Peng, Yimin Dong, Fuben Liao, Meipeng Zhu, Pengju Wang, Shi-An Hu, Peixuan Hu, Jia Wang, Zheming Liu, Kehan Song, Feng Li","doi":"10.1016/j.ymthe.2025.01.040","DOIUrl":"10.1016/j.ymthe.2025.01.040","url":null,"abstract":"<p><p>Tumor necrosis factor receptor-associated factor 1 (TRAF1) is a crucial signaling adaptor involved in multiple cellular events. However, its role in regulating osteoclastogenesis and energy metabolism remains unclear. Here, we report that TRAF1 promotes osteoclastogenesis and oxidative phosphorylation (OXPHOS). Employing RNA sequencing, we found that TRAF1 is markedly upregulated during osteoclastogenesis and is positively associated with osteoporosis. TRAF1 knockout inhibits osteoclastogenesis and increases bone mass in both normal and ovariectomized adult mice without affecting bone mass in childhood. Furthermore, TRAF1 promotes osteoclast OXPHOS by increasing the phosphorylation level of AKT. Mechanistically, TRAF1 functions to inhibit TRAF2-induced ubiquitination of Gβl, a known activator of AKT, and further upregulates AKT phosphorylation. Rescue experiments revealed that the inhibitory effects of TRAF1 knockout on osteoclastogenesis, OXPHOS, and bone mass are dependent on AKT. Collectively, our findings uncover a previously unrecognized function of TRAF1 in regulating osteoclastogenesis and energy metabolism, and establish a novel TRAF1-AKT-OXPHOS axis in osteoclasts.</p>","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":" ","pages":""},"PeriodicalIF":12.1,"publicationDate":"2025-01-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143040300","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Molecular TherapyPub Date : 2025-01-25DOI: 10.1016/j.ymthe.2025.01.038
Anders Schlosser, Bartosz Pilecki, Claire Allen, Andrew V Benest, Amy P Lynch, Jing Hua, Nikita Ved, Zoe Blackley, Thomas L Andersen, Dorle Hennig, Jonas H Graversen, Sören Möller, Sofie Skallerup, Maria Ormhøj, Clemens Lange, Hansjürgen T Agostini, Jakob Grauslund, Steffen Heegaard, Ivanka Dacheva, Michael Koss, Wenzheng Hu, Bibiana Iglesias, Matthew S Lawrence, Hans Christian Beck, Lasse Bach Steffensen, Nick S Laursen, Gregers R Andersen, Uffe Holmskov, David O Bates, Grith L Sorensen
{"title":"Pharmacological blocking of microfibrillar-associated protein 4 reduces retinal neoangiogenesis and vascular leakage.","authors":"Anders Schlosser, Bartosz Pilecki, Claire Allen, Andrew V Benest, Amy P Lynch, Jing Hua, Nikita Ved, Zoe Blackley, Thomas L Andersen, Dorle Hennig, Jonas H Graversen, Sören Möller, Sofie Skallerup, Maria Ormhøj, Clemens Lange, Hansjürgen T Agostini, Jakob Grauslund, Steffen Heegaard, Ivanka Dacheva, Michael Koss, Wenzheng Hu, Bibiana Iglesias, Matthew S Lawrence, Hans Christian Beck, Lasse Bach Steffensen, Nick S Laursen, Gregers R Andersen, Uffe Holmskov, David O Bates, Grith L Sorensen","doi":"10.1016/j.ymthe.2025.01.038","DOIUrl":"10.1016/j.ymthe.2025.01.038","url":null,"abstract":"<p><p>Neovascular age-related macular degeneration and diabetic macular edema are leading causes of vision loss evoked by retinal neovascularization and vascular leakage. The glycoprotein microfibrillar-associated protein 4 (MFAP4) is an integrin α<sub>V</sub>β<sub>3/5/6</sub> ligand present in the extracellular matrix. Single-cell transcriptomics reveal MFAP4 expression in cell types in close proximity to vascular endothelial cells, including choroidal vascular mural cells, retinal astrocytes, and Müller cells. Binding of the anti-MFAP4 antibody, hAS0326, makes MFAP4 inaccessible for integrin receptor interaction, and thereby hAS0326 blocked endothelial cell motility in vitro. Intravitreal hAS0326 inhibited retinal vascular lesion area and neovessel volume in a laser-induced choroidal neovascularization mouse model, vascular permeability in streptozotocin-induced retinopathy, and vascular leakage area in a chronic non-human primate model of DL-2-aminoadipic acid-induced retinopathy. One dose of hAS0326 showed duration of efficacy of at least 12 weeks in the latter model. Moreover, hAS0326 treatment significantly enriched Gene Ontology terms involving reduction of integrin binding. Our data suggest that hAS0326 constitutes a promising treatment of neovascularization and vascular leakage in retinal diseases.</p>","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":" ","pages":""},"PeriodicalIF":12.1,"publicationDate":"2025-01-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143040292","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"GITRL enhances cytotoxicity and persistence of CAR-T cells in cancer therapy.","authors":"Binghe Tan, Chuntian Tu, Hao Xiong, Yongqian Xu, Xiujuan Shi, Xiaolin Zhang, Ruijie Yang, Na Zhang, Boxu Lin, Mingyao Liu, Juliang Qin, Bing Du","doi":"10.1016/j.ymthe.2025.01.036","DOIUrl":"10.1016/j.ymthe.2025.01.036","url":null,"abstract":"<p><p>Chimeric antigen receptor (CAR)-T cell therapy has achieved remarkable clinical success in treating hematological malignancies. However, its clinical efficacy in solid tumors is less satisfactory, partially due to poor in vivo expansion and the limited persistence of CAR-T cells. Here, we demonstrated that the overexpression of GITR ligand enhances the anti-tumor activity of CAR-T cells. Compared to prostate-specific membrane antigen-BB-Z (PSMA-BB-Z) CAR-T, PSMA-BB-Z-GITRL CAR-T cells have much more interferon (IFN)-γ, TNF-α, and interleukin (IL)-9 secretion, a higher proportion of central memory T (T<sub>CM</sub>) cells and T helper 9 (Th9) cells, less expression of exhaustion markers, and robust proliferation capacity. Consequently, PSMA-BB-Z-GITRL CAR-T cells exhibited more potent anti-tumor activity against established solid tumors in vivo than PSMA-BB-Z CAR-T cells. The results of the in vivo persistence experiment also indicated that PSMA-BB-Z-GITRL CAR-T cells exhibited much more retention in mouse blood, spleen, and tumor tissue than PSMA-BB-Z CAR-T cells 15 days after CAR-T cell therapy. In addition, PSMA-BB-Z-GITRL CAR-T cells produce higher levels of IFN-γ, TNF-α, and IL-9 in mouse blood, exhibiting a higher proportion of T<sub>CM</sub> cells and a lower proportion of Treg cells compared to PSMA-BB-Z CAR-T cells. Our results demonstrate that the overexpression of GITRL has important implications for improving CAR-T cell-based human solid tumor immunotherapy.</p>","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":" ","pages":""},"PeriodicalIF":12.1,"publicationDate":"2025-01-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143040265","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Molecular TherapyPub Date : 2025-01-25DOI: 10.1016/j.ymthe.2025.01.039
Wooil Choi, Dong Jun Park, Robert A Dorschner, Keita Nakatsutsumi, Michelle Yi, Brian P Eliceiri
{"title":"CDK1-loaded extracellular vesicles promote cell cycle to reverse impaired wound healing in diabetic obese mice.","authors":"Wooil Choi, Dong Jun Park, Robert A Dorschner, Keita Nakatsutsumi, Michelle Yi, Brian P Eliceiri","doi":"10.1016/j.ymthe.2025.01.039","DOIUrl":"10.1016/j.ymthe.2025.01.039","url":null,"abstract":"<p><p>Small extracellular vesicles (sEVs) mediate intercellular signaling to coordinate the proliferation of cell types that promote re-epithelialization of skin following injury. Cyclin-dependent kinase 1 (CDK1) drives cell division and is a key regulator of entry to the cell cycle. To understand the potential of sEV-mediated delivery of CDK1 to reverse impaired wound healing, we generated CDK1-loaded sEVs (CDK1-sEVs) and evaluated their ability to mediate cell proliferation, re-epithelialization, and downstream signaling responses in the wound bed. We found that treatment of human keratinocytes with CDK1-sEVs increased phosphorylation of the CDK1 target, eukaryotic translation inhibition factor 4E-binding protein 1 (4E-BP1), and histone H3 within 24 h via AKT and ERK phosphorylation, driving increased proliferation and cell migration. Treatment of the wound bed of diabetic obese mice, a model of delayed wound healing, with a single dose of CDK1-sEVs accelerated wound closure, increased re-epithelialization, and promoted the proliferation of keratinocytes. These studies show that delivery of CDK1 by sEVs can stimulate selective and transient proliferation of cell types that increase re-epithelialization and promote proliferation of keratinocytes to accelerate wound healing.</p>","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":" ","pages":""},"PeriodicalIF":12.1,"publicationDate":"2025-01-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143046977","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Molecular TherapyPub Date : 2025-01-25DOI: 10.1016/j.ymthe.2025.01.034
Sumit S Verma, Chandan K Sen, Rajneesh Srivastava, Surya C Gnyawali, Parul Katiyar, Ajay K Sahi, Manishekhar Kumar, Yashika Rustagi, Sheng Liu, Diksha Pandey, Ahmed S Abouhashem, Leila N W Fehme, Sedat Kacar, Sujit K Mohanty, Julie Faden-McCormack, Michael P Murphy, Sashwati Roy, Jun Wan, Mervin C Yoder, Kanhaiya Singh
{"title":"Tissue nanotransfection-based endothelial PLCγ2-targeted epigenetic gene editing rescues perfusion and diabetic ischemic wound healing.","authors":"Sumit S Verma, Chandan K Sen, Rajneesh Srivastava, Surya C Gnyawali, Parul Katiyar, Ajay K Sahi, Manishekhar Kumar, Yashika Rustagi, Sheng Liu, Diksha Pandey, Ahmed S Abouhashem, Leila N W Fehme, Sedat Kacar, Sujit K Mohanty, Julie Faden-McCormack, Michael P Murphy, Sashwati Roy, Jun Wan, Mervin C Yoder, Kanhaiya Singh","doi":"10.1016/j.ymthe.2025.01.034","DOIUrl":"10.1016/j.ymthe.2025.01.034","url":null,"abstract":"<p><p>Diabetic wounds are complicated by underlying peripheral vasculopathy. Reliance on vascular endothelial growth factor (VEGF) therapy to improve perfusion makes logical sense, yet clinical study outcomes on rescuing diabetic wound vascularization have yielded disappointing results. Our previous work has identified that low endothelial phospholipase Cγ2 (PLCγ2) expression hinders the therapeutic effect of VEGF on the diabetic ischemic limb. In this work, guided by single-cell RNA sequencing of human wound edge, we test the efficacy of gene-targeted therapeutic demethylation intending to improve VEGF-mediated neovascularization. PLCγ2 expression was diminished in all five identified diabetic wound-edge endothelial subclusters encompassing arterial, venous, and capillary cells. Such low expression was associated with hypermethylated PLCγ2 promoter. PLCγ2 promoter was also hypermethylated at murine diabetic ischemic wound edge. To specifically demethylate endothelial PLCγ2 promoter during VEGF therapy, a CRISPR-dCas9-based demethylation cocktail was delivered to the ischemic wound edge using tissue nanotransfection (TNT) technology. Demethylation-based upregulation of PLCγ2 during VEGF therapy improved wound tissue blood flow with an increased abundance of von Willebrand factor (vWF)<sup>+</sup>/PLCγ2<sup>+</sup> vascular tissue elements by activating p44/p42-mitogen-activated protein kinase (MAPK) → hypoxia-inducible factor [HIF]-1α pathway. Taken together, TNT-based delivery of plasmids to demethylate the PLCγ2 gene promoter activity led to significant improvements in VEGF therapy for cutaneous diabetic wounds, resulting in better perfusion and accelerated wound closure.</p>","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":" ","pages":""},"PeriodicalIF":12.1,"publicationDate":"2025-01-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143040295","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Molecular TherapyPub Date : 2025-01-24DOI: 10.1016/j.ymthe.2025.01.018
Xiaole Wang, Jing Peng
{"title":"Gene therapy in China: From a clinician's perspective.","authors":"Xiaole Wang, Jing Peng","doi":"10.1016/j.ymthe.2025.01.018","DOIUrl":"https://doi.org/10.1016/j.ymthe.2025.01.018","url":null,"abstract":"","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":" ","pages":""},"PeriodicalIF":12.1,"publicationDate":"2025-01-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143040262","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}