Cancer research最新文献

{"title":"Pharmacologic Blockade of a Pioneer Transcription Factor.","authors":"Katerina Cermakova, H Courtney Hodges","doi":"10.1158/0008-5472.CAN-24-3957","DOIUrl":"10.1158/0008-5472.CAN-24-3957","url":null,"abstract":"<p><p>Cancers frequently co-opt lineage-specific transcription factors (TF) utilized in normal development to sustain proliferation. However, the effects of these TFs on tumor development depend considerably on where in the genome they bind. A new article by Taylor and colleagues expands on previously developed diamidine compounds that obstruct the DNA binding sites of the pioneer TF PU.1 (SPI1) in acute myeloid leukemia. Immobilization and sequencing of genomic DNA targeted by these compounds revealed that these inhibitors alter the genomic binding patterns of PU.1. The authors report that their strategy constrains the genomic binding preferences of PU.1, leading to redistribution of PU.1 to promoters and other gene-proximal regions with elevated guanine/cytosine content. In this study, we discuss recent developments for targeting PU.1 in hematologic malignancies. We also explore the shared functional roles of PU.1 and SWI/SNF ATP-dependent chromatin remodeling complexes, which not only work together to sustain the enhancer landscape needed for tumor cell proliferation but also play key roles in nontumor settings.</p>","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":" ","pages":"4124-4125"},"PeriodicalIF":12.5,"publicationDate":"2024-12-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142543886","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":"Correction: Single-Cell Transcriptomic Heterogeneity in Invasive Ductal and Lobular Breast Cancer Cells.","authors":"Fangyuan Chen, Kai Ding, Nolan Priedigkeit, Ashuvinee Elangovan, Kevin M Levine, Neil Carleton, Laura Savariau, Jennifer M Atkinson, Steffi Oesterreich, Adrian V Lee","doi":"10.1158/0008-5472.CAN-24-3940","DOIUrl":"https://doi.org/10.1158/0008-5472.CAN-24-3940","url":null,"abstract":"","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"84 24","pages":"4298"},"PeriodicalIF":12.5,"publicationDate":"2024-12-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142827493","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":"Induction of the TEAD Coactivator VGLL1 by Estrogen Receptor-Targeted Therapy Drives Resistance in Breast Cancer.","authors":"Carolina Gemma, Chun-Fui Lai, Anup K Singh, Antonino Belfiore, Neil Portman, Heloisa Z Milioli, Manikandan Periyasamy, Sara Raafat, Alyssa J Nicholls, Claire M Davies, Naina R Patel, Georgia M Simmons, Hailing Fan, Van T M Nguyen, Luca Magnani, Emad Rakha, Lesley-Ann Martin, Elgene Lim, R Charles Coombes, Giancarlo Pruneri, Laki Buluwela, Simak Ali","doi":"10.1158/0008-5472.CAN-24-0013","DOIUrl":"10.1158/0008-5472.CAN-24-0013","url":null,"abstract":"<p><p>Resistance to endocrine therapies (ET) is common in estrogen receptor (ER)-positive breast cancer, and most relapsed patients die with ET-resistant disease. Although genetic mutations provide explanations for some relapses, mechanisms of resistance remain undefined in many cases. Drug-induced epigenetic reprogramming has been shown to provide possible routes to resistance. By analyzing histone H3 lysine 27 acetylation profiles and transcriptional reprogramming in models of ET resistance, we discovered that selective ER degraders, such as fulvestrant, promote expression of vestigial-like 1 (VGLL1), a coactivator for TEF-1 and AbaA domain (TEAD) transcription factors. VGLL1, acting via TEADs, promoted the expression of genes that drive the growth of fulvestrant-resistant breast cancer cells. Pharmacological disruption of VGLL1-TEAD4 interaction inhibited VGLL1/TEAD-induced transcriptional programs to prevent the growth of resistant cells. EGFR was among the VGLL1/TEAD-regulated genes, and VGLL1-directed EGFR upregulation sensitized fulvestrant-resistant breast cancer cells to EGFR inhibitors. Taken together, these findings identify VGLL1 as a transcriptional driver in ET resistance and advance therapeutic possibilities for relapsed ER+ breast cancer patients. Significance: Transcriptional reprogramming mediated by the upregulation of the TEAD coactivator VGLL1 confers resistance to estrogen receptor degraders in breast cancer but provides alternative therapeutic options for this clinically important patient group.</p>","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":" ","pages":"4283-4297"},"PeriodicalIF":12.5,"publicationDate":"2024-12-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7616691/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142364507","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"C-Reactive Protein Facilitates Premetastatic Niche Formation in the Lungs.","authors":"Jonas Saal, Niklas Klümper, Michael Hölzel","doi":"10.1158/0008-5472.CAN-24-3394","DOIUrl":"https://doi.org/10.1158/0008-5472.CAN-24-3394","url":null,"abstract":"<p><p>C-reactive protein (CRP) has long been recognized as a marker of inflammation, but its evolving role in immunomodulation and cancer has increasingly been recognized. In recent years, multiple studies have explored CRP as a biomarker for prognosis and therapy response, particularly in the context of cancer immunotherapy. In this issue of Cancer Research, Feng and colleagues investigate the role of CRP in the development of lung metastasis. They provide evidence for a direct role of CRP acting together with commensal bacteria to instruct an immune-tolerant state of pulmonary macrophages through Fc gamma receptor IIb signaling. By suppressing immune surveillance in the lungs, CRP facilitates the formation of a premetastatic niche, allowing circulating tumor cells to establish metastases. See related article by Feng et al., p. 4184.</p>","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"84 24","pages":"4121-4123"},"PeriodicalIF":12.5,"publicationDate":"2024-12-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142827496","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":"BEEx is An Open-Source Tool that Evaluates Batch Effects in Medical Images to Enable Multi-center Studies.","authors":"Yuxin Wu, Xiongjun Xu, Yuan Cheng, Xiuming Zhang, Fanxi Liu, Zhenhui Li, Lei Hu, Anant Madabhushi, Peng Gao, Zaiyi Liu, Cheng Lu","doi":"10.1158/0008-5472.CAN-23-3846","DOIUrl":"https://doi.org/10.1158/0008-5472.CAN-23-3846","url":null,"abstract":"<p><p>The batch effect is a nonbiological variation that arises from technical differences across different batches of data during the data generation process for acquisition-related reasons, such as collection of images at different sites or using different scanners. This phenomenon can affect the robustness and generalizability of computational pathology- or radiology-based cancer diagnostic models, especially in multi-center studies. To address this issue, we developed an open-source platform, Batch Effect Explorer (BEEx), that is designed to qualitatively and quantitatively determine whether batch effects exist among medical image datasets from different sites. A suite of tools was incorporated into BEEx that provide visualization and quantitative metrics based on intensity, gradient, and texture features to allow users to determine whether there are any image variables or combinations of variables that can distinguish datasets from different sites in an unsupervised manner. BEEx was designed to support various medical imaging techniques, including microscopy and radiology. Four use cases clearly demonstrated the ability of BEEx to identify batch effects and validated the effectiveness of rectification methods for batch effect reduction. Overall, BEEx is a scalable and versatile framework designed to read, process, and analyze a wide range of medical images to facilitate the identification and mitigation of batch effects, which can enhance the reliability and validity of image-based studies.</p>","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":" ","pages":""},"PeriodicalIF":12.5,"publicationDate":"2024-12-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142805805","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":"Hypoxia-Induced Senescent Fibroblasts Secrete IGF1 to Promote Cancer Stemness in Esophageal Squamous Cell Carcinoma","authors":"Zhengjie Ou, Liang Zhu, Xinjie Chen, Tianyuan Liu, Guoyu Cheng, Rucheng Liu, Shaosen Zhang, Wen Tan, Dongxin Lin, Chen Wu","doi":"10.1158/0008-5472.can-24-1185","DOIUrl":"https://doi.org/10.1158/0008-5472.can-24-1185","url":null,"abstract":"Cancer-associated fibroblasts (CAFs) contribute to cancer initiation and progression and play a pivotal role in therapeutic response and patient prognosis. CAFs exhibit functional and phenotypic heterogeneity, highlighting the need to clarify the specific subtypes of CAFs to facilitate the development of targeted therapies against pro-tumorigenic CAFs. Here, using single-cell RNA sequencing on patient samples of esophageal squamous cell carcinoma (ESCC), we identified a CAF subcluster associated with tumor stemness that was enriched in genes associated with hypoxia and senescence. The CAF subpopulation, termed as hypoxia-induced senescent fibroblasts (hsCAFs), displayed high secretion of insulin-like growth factor 1 (IGF1). The hsCAFs inhibited AMP-activated protein kinase (AMPK) activity in cancer cells via IGF1 to promote tumor stemness. The formation of hsCAFs was induced by the synergetic effect of hypoxia and cancer cells. Activation of nuclear factor erythroid 2-related factor 2 (NRF2) in cancer cells under hypoxia drove interleukin-1 alpha (IL-1α) production to trigger CAF senescence and IGF1 secretion via nuclear factor I A (NFIA). Knockout of IGF1 in CAFs or NRF2 in ESCC cells suppressed the tumor growth and chemotherapy resistance induced by CAFs in vivo. Importantly, patients with high proportions of hsCAFs showed poor survival and a worse response to chemotherapy. In summary, these findings identify a hsCAF subpopulation generated by interplay between cancer cells and CAFs under hypoxic conditions that promotes ESCC stemness and reveal targeting hsCAFs as an effective therapeutic strategy against chemotherapy-resistant ESCC.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"14 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2024-12-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142809628","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":"Therapeutic Targeting and Structural Characterization of a Sotorasib-Modified KRAS G12C-MHC I complex Demonstrates the Antitumor Efficacy of Hapten-Based Strategies.","authors":"Apurva Pandey, Peter J Rohweder, Lieza M Chan, Chayanid Ongpipattanakul, Dong Hee Chung, Bryce Paolella, Fiona M Quimby, Ngoc Nguyen, Kliment A Verba, Michael J Evans, Charles S Craik","doi":"10.1158/0008-5472.CAN-24-2450","DOIUrl":"https://doi.org/10.1158/0008-5472.CAN-24-2450","url":null,"abstract":"<p><p>Antibody-based therapies have emerged as a powerful strategy for the management of diverse cancers. Unfortunately, tumor-specific antigens remain challenging to identify and target. Recent work established that inhibitor-modified peptide adducts derived from KRAS G12C are competent for antigen presentation via MHC I and can be targeted by antibody-based therapeutics, offering a means to directly target an intracellular oncoprotein at the cell surface with combination therapies. Here, we validated antigen display of \"haptenated\" KRAS G12C peptide fragments on tumors in mouse models treated with the FDA-approved KRAS G12C covalent inhibitor Sotorasib using PET/CT imaging of an 89Zr-labeled P1B7 IgG antibody, which selectively binds Sotorasib-modified KRAS G12C MHC I complexes. Targeting this peptide-MHC I complex with radioligand therapy using 225Ac- or 177Lu-P1B7 IgG effectively inhibited tumor growth in combination with Sotorasib. Elucidation of the 3.1 Å cryo-EM structure of P1B7 bound to a haptenated KRAS G12C peptide-MHC I complex confirmed that the Sotorasib-modified KRAS G12C peptide is presented via a canonical binding pose and showed that P1B7 binds the complex in a T-cell receptor-like manner. Together, these findings demonstrate the potential value of targeting unique oncoprotein-derived, haptenated MHC I complexes with radioligand therapeutics and provide a structural framework for developing next generation antibodies.</p>","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":" ","pages":""},"PeriodicalIF":12.5,"publicationDate":"2024-12-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142799399","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":"Imlunestrant is an Oral, Brain-Penetrant Selective Estrogen Receptor Degrader with Potent Antitumor Activity in ESR1 Wildtype and Mutant Breast Cancer","authors":"Shripad V. Bhagwat, Cecilia Mur, Matthew Vandekopple, Baohui Zhao, Weihua Shen, Carlos Marugán, Andrew Capen, Lisa Kindler, Jennifer R. Stephens, Lysiane Huber, Mark A. Castanares, David Garcia-Tapia, Jeff D. Cohen, Jolie Bastian, Brian Mattioni, Eunice Yuen, Thomas K. Baker, Vivian Rodriguez Cruz, Dongling Fei, Jason R. Manro, Nicholas Pulliam, Michele S. Dowless, Maria Jesus. Ortiz Ruiz, Chunping Yu, Loredana Puca, Anke Klippel, Francesca Bacchion, Roohi Ismail-Khan, Vanessa Rodrik-Outmezguine, Sheng-Bin Peng, María Jose Lallena, Xueqian Gong, Alfonso de Dios","doi":"10.1158/0008-5472.can-24-2608","DOIUrl":"https://doi.org/10.1158/0008-5472.can-24-2608","url":null,"abstract":"Targeting of the estrogen receptor (ER) by anti-estrogens is the standard-of-care for patients with ER+ HER2- advanced/metastatic breast cancer. While anti-estrogens that degrade ERα (fulvestrant) or block estrogen production (aromatase inhibitors) have improved patient outcomes, clinically important challenges remain related to drug administration, limited bioavailability, lack of brain exposure, and acquired resistance due to ESR1 mutations. These limitations indicate a need for more robust ER-targeted therapies. Here, we discovered and characterized imlunestrant, a next-generation potent, brain-penetrant oral selective estrogen receptor degrader (SERD). Imlunestrant degraded ERα and decreased ERα-mediated gene expression both in vitro and in vivo. Cell proliferation and tumor growth in ESR1 wildtype and mutant models were significantly inhibited by imlunestrant. Combining imlunestrant with abemaciclib (CDK4/6 inhibitor), alpelisib (PI3K inhibitor), or everolimus (mTOR inhibitor) further enhanced tumor growth inhibition, regardless of ESR1 mutational status. In an ER+ breast cancer intracranial tumor model, imlunestrant prolonged survival compared to vehicle or alternative SERD therapies. Together, these finding support the potential of imlunestrant to degrade ERα and suppress the growth of ESR1 wildtype and mutant breast cancer, including brain metastatic tumors.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"5 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2024-12-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142796940","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":"Plasma cell-free DNA chromatin immunoprecipitation profiling depicts phenotypic and clinical heterogeneity in advanced prostate cancer","authors":"Joonatan Sipola, Aslı D. Munzur, Edmond M. Kwan, Clara C. Y. Seo, Benjamin J. Hauk, Karan Parekh, Yi Jou (Ruby) Liao, Cecily Q. Bernales, Gráinne Donnellan, Ingrid Bloise, Emily Fung, Sarah W.S. Ng, Gang Wang, Gillian Vandekerkhove, Matti Nykter, Matti Annala, Corinne Maurice-Dror, Kim N. Chi, Cameron Herberts, Alexander W. Wyatt, David Y. Takeda","doi":"10.1158/0008-5472.can-24-2052","DOIUrl":"https://doi.org/10.1158/0008-5472.can-24-2052","url":null,"abstract":"Cell phenotype underlies prostate cancer presentation and treatment resistance and can be regulated by epigenomic features. However, the osteotropic tendency of prostate cancer limits access to metastatic tissue, meaning most prior insights into prostate cancer chromatin biology are from preclinical models that do not fully represent disease complexity. Noninvasive chromatin immunoprecipitation of histones in plasma cell-free in humans may enable capture of disparate prostate cancer phenotypes. Here, we analyzed activating promoter- and enhancer-associated H3K4me2 from cfDNA in metastatic prostate cancer enriched for divergent patterns of metastasis and diverse clinical presentation. H3K4me2 density across prostate cancer genes, accessible chromatin, and lineage-defining transcription factor binding sites correlated strongly with circulating tumor DNA (ctDNA) fraction—demonstrating capture of prostate cancer-specific biology and informing the development of a statistical framework to adjust for ctDNA fraction. Chromatin hallmarks mirrored synchronously measured clinico-genomic features: bone versus liver-predominant disease, serum PSA, biopsy-confirmed histopathological subtype, and RB1 deletions convergently indicated phenotype segregation along an axis of differential androgen receptor activity and neuroendocrine identity. Detection of lineage switching after sequential progression on systemic therapy in select patients indicates potential utility for individualized resistance monitoring. Epigenomic footprints of metastasis-induced normal tissue destruction were evident in bulk cfDNA from two patients. Finally, a public epigenomic resource was generated using a distinct chromatin marker that has not been widely investigated in prostate cancer. These results provide insight into the adaptive molecular landscape of aggressive prostate cancer and endorse plasma cfDNA chromatin profiling as a biomarker source and biological discovery tool.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"140 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2024-12-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142796990","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":"Adenosine Uptake through the Nucleoside Transporter ENT1 Suppresses Antitumor Immunity and T Cell Pyrimidine Synthesis","authors":"David Allard, Jeanne Cormery, Salma Bricha, Camille Fuselier, Farnoosh Abbas Aghababazadeh, Lucie Giraud, Emma Skora, Benjamin Haibe-Kains, John Stagg","doi":"10.1158/0008-5472.can-24-1875","DOIUrl":"https://doi.org/10.1158/0008-5472.can-24-1875","url":null,"abstract":"Immunosuppression by adenosine is an important cancer immune checkpoint. Extracellular adenosine signals through specific receptors and can be transported across the cell membrane through nucleoside transporters. While adenosine receptors are well-known to regulate tumor immunity, the impact of adenosine transporters remains unexplored. In this study, we investigated the effect on tumor immunity of equilibrative nucleoside transporter-1 (ENT1), the major regulator of extracellular adenosine concentrations. Blocking or deleting host ENT1 significantly enhanced CD8+ T cell-dependent antitumor responses. Tumors inoculated into ENT1-deficient mice showed increased infiltration of effector CD8+ T cells with an enhanced cytotoxic transcriptomic profile and significant upregulation of granzyme B, IFN-γ, IL-2, TNF-α, and CXCL10. ENT1-deficiency was further associated with decreased tumor-infiltrating T regulatory cells and CD206high macrophages and suppressed CCL17 production. ENT1-deficiency notably potentiated the therapeutic activity of PD-1 blockade. T cells upregulated ENT1 upon activation, and blocking ENT1 enhanced their function when co-cultured with cognate antigen/HLA-matched melanoma cells. Mechanistically, ENT1-mediated adenosine uptake inhibited the activity of phosphoribosyl pyrophosphate synthetase (PRPS) in activated T cells, thereby suppressing production of uridine 5′-monophosphate (UMP) and its derivatives required for DNA and RNA synthesis. In summary, this study identified ENT1-mediated adenosine uptake as an important mechanism of adenosine-mediated immunosuppression and pyrimidine starvation that can be targeted to enhance antitumor T cell responses.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"9 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2024-12-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142796942","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}