NAR cancerPub Date : 2024-05-31eCollection Date: 2024-06-01DOI: 10.1093/narcan/zcae025
Anne Cammas, Alice Desprairies, Erik Dassi, Stefania Millevoi
{"title":"The shaping of mRNA translation plasticity by RNA G-quadruplexes in cancer progression and therapy resistance.","authors":"Anne Cammas, Alice Desprairies, Erik Dassi, Stefania Millevoi","doi":"10.1093/narcan/zcae025","DOIUrl":"10.1093/narcan/zcae025","url":null,"abstract":"<p><p>Translational reprogramming in response to oncogenic signaling or microenvironmental stress factors shapes the proteome of cancer cells, enabling adaptation and phenotypic changes underlying cell plasticity, tumor progression and response to cancer therapy. Among the mechanisms regulating translation are RNA G-quadruplexes (RG4s), non-canonical four-stranded structures whose conformational modulation by small molecule ligands and RNA-binding proteins affects the expression of cancer proteins. Here, we discuss the role of RG4s in the regulation of mRNA translation by focusing on paradigmatic examples showing their contribution to adaptive mechanisms of mRNA translation in cancer.</p>","PeriodicalId":94149,"journal":{"name":"NAR cancer","volume":"6 2","pages":"zcae025"},"PeriodicalIF":0.0,"publicationDate":"2024-05-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11140630/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141201333","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}
NAR cancerPub Date : 2024-05-31eCollection Date: 2024-06-01DOI: 10.1093/narcan/zcae026
Mélanie Mahé, Tiffany Rios-Fuller, Olga Katsara, Robert J Schneider
{"title":"Non-canonical mRNA translation initiation in cell stress and cancer.","authors":"Mélanie Mahé, Tiffany Rios-Fuller, Olga Katsara, Robert J Schneider","doi":"10.1093/narcan/zcae026","DOIUrl":"10.1093/narcan/zcae026","url":null,"abstract":"<p><p>The now well described canonical mRNA translation initiation mechanism of m<sup>7</sup>G 'cap' recognition by cap-binding protein eIF4E and assembly of the canonical pre-initiation complex consisting of scaffolding protein eIF4G and RNA helicase eIF4A has historically been thought to describe all cellular mRNA translation. However, the past decade has seen the discovery of alternative mechanisms to canonical eIF4E mediated mRNA translation initiation. Studies have shown that non-canonical alternate mechanisms of cellular mRNA translation initiation, whether cap-dependent or independent, serve to provide selective translation of mRNAs under cell physiological and pathological stress conditions. These conditions typically involve the global downregulation of canonical eIF4E1/cap-mediated mRNA translation, and selective translational reprogramming of the cell proteome, as occurs in tumor development and malignant progression. Cancer cells must be able to maintain physiological plasticity to acquire a migratory phenotype, invade tissues, metastasize, survive and adapt to severe microenvironmental stress conditions that involve inhibition of canonical mRNA translation initiation. In this review we describe the emerging, important role of non-canonical, alternate mechanisms of mRNA translation initiation in cancer, particularly in adaptation to stresses and the phenotypic cell fate changes involved in malignant progression and metastasis. These alternate translation initiation mechanisms provide new targets for oncology therapeutics development.</p>","PeriodicalId":94149,"journal":{"name":"NAR cancer","volume":"6 2","pages":"zcae026"},"PeriodicalIF":0.0,"publicationDate":"2024-05-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11140632/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141201327","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}
NAR cancerPub Date : 2024-05-20eCollection Date: 2024-06-01DOI: 10.1093/narcan/zcae023
Anwesha Dasgupta, John R Prensner
{"title":"Upstream open reading frames: new players in the landscape of cancer gene regulation.","authors":"Anwesha Dasgupta, John R Prensner","doi":"10.1093/narcan/zcae023","DOIUrl":"10.1093/narcan/zcae023","url":null,"abstract":"<p><p>The translation of RNA by ribosomes represents a central biological process and one of the most dysregulated processes in cancer. While translation is traditionally thought to occur exclusively in the protein-coding regions of messenger RNAs (mRNAs), recent transcriptome-wide approaches have shown abundant ribosome activity across diverse stretches of RNA transcripts. The most common type of this kind of ribosome activity occurs in gene leader sequences, also known as 5' untranslated regions (UTRs) of the mRNA, that precede the main coding sequence. Translation of these upstream open reading frames (uORFs) is now known to occur in upwards of 25% of all protein-coding genes. With diverse functions from RNA regulation to microprotein generation, uORFs are rapidly igniting a new arena of cancer biology, where they are linked to cancer genetics, cancer signaling, and tumor-immune interactions. This review focuses on the contributions of uORFs and their associated 5'UTR sequences to cancer biology.</p>","PeriodicalId":94149,"journal":{"name":"NAR cancer","volume":"6 2","pages":"zcae023"},"PeriodicalIF":0.0,"publicationDate":"2024-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11106035/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141077502","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}
NAR cancerPub Date : 2024-05-20eCollection Date: 2024-06-01DOI: 10.1093/narcan/zcae021
Pia Hoellerbauer, Megan Kufeld, Sonali Arora, Kelly Mitchell, Emily J Girard, Jacob A Herman, James M Olson, Patrick J Paddison
{"title":"<i>FBXO42</i> activity is required to prevent mitotic arrest, spindle assembly checkpoint activation and lethality in glioblastoma and other cancers.","authors":"Pia Hoellerbauer, Megan Kufeld, Sonali Arora, Kelly Mitchell, Emily J Girard, Jacob A Herman, James M Olson, Patrick J Paddison","doi":"10.1093/narcan/zcae021","DOIUrl":"10.1093/narcan/zcae021","url":null,"abstract":"<p><p>Glioblastoma (GBM) is the most common and aggressive brain tumor in adults. To identify genes differentially required for the viability of GBM stem-like cells (GSCs), we performed functional genomic lethality screens comparing GSCs and control human neural stem cells. Among top-scoring hits in a subset of GBM cells was the F-box-containing gene <i>FBXO42</i>, which was also predicted to be essential in ∼15% of cell lines derived from a broad range of cancers. Mechanistic studies revealed that, in sensitive cells, <i>FBXO42</i> activity prevents chromosome alignment defects, mitotic cell cycle arrest and cell death. The cell cycle arrest, but not the cell death, triggered by <i>FBXO42</i> inactivation could be suppressed by brief exposure to a chemical inhibitor of Mps1, a key spindle assembly checkpoint (SAC) kinase. <i>FBXO42</i>'s cancer-essential function requires its F-box and Kelch domains, which are necessary for FBXO42's substrate recognition and targeting by SCF (SKP1-CUL1-F-box protein) ubiquitin ligase complex. However, none of FBXO42's previously proposed targets, including ING4, p53 and RBPJ, were responsible for the observed phenotypes. Instead, our results suggest that FBOX42 alters the activity of one or more proteins that perturb chromosome-microtubule dynamics in cancer cells, which in turn leads to induction of the SAC and cell death.</p>","PeriodicalId":94149,"journal":{"name":"NAR cancer","volume":"6 2","pages":"zcae021"},"PeriodicalIF":3.4,"publicationDate":"2024-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11106029/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141077501","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}
NAR cancerPub Date : 2024-03-18eCollection Date: 2024-03-01DOI: 10.1093/narcan/zcae013
Alexandra M Blee, Kaitlyn S Gallagher, Hyun-Suk Kim, Mihyun Kim, Suhas S Kharat, Christina R Troll, Areetha D'Souza, Jiyoung Park, P Drew Neufer, Orlando D Schärer, Walter J Chazin
{"title":"XPA tumor variant leads to defects in NER that sensitize cells to cisplatin.","authors":"Alexandra M Blee, Kaitlyn S Gallagher, Hyun-Suk Kim, Mihyun Kim, Suhas S Kharat, Christina R Troll, Areetha D'Souza, Jiyoung Park, P Drew Neufer, Orlando D Schärer, Walter J Chazin","doi":"10.1093/narcan/zcae013","DOIUrl":"10.1093/narcan/zcae013","url":null,"abstract":"<p><p>Nucleotide excision repair (NER) reduces efficacy of treatment with platinum (Pt)-based chemotherapy by removing Pt lesions from DNA. Previous study has identified that missense mutation or loss of the NER genes Excision Repair Cross Complementation Group 1 and 2 (<i>ERCC1</i> and <i>ERCC2</i>) leads to improved patient outcomes after treatment with Pt-based chemotherapies. Although most NER gene alterations found in patient tumors are missense mutations, the impact of mutations in the remaining nearly 20 NER genes is unknown. Towards this goal, we previously developed a machine learning strategy to predict genetic variants in an essential NER protein, Xeroderma Pigmentosum Complementation Group A (XPA), that disrupt repair. In this study, we report in-depth analyses of a subset of the predicted variants, including <i>in vitro</i> analyses of purified recombinant protein and cell-based assays to test Pt agent sensitivity in cells and determine mechanisms of NER dysfunction. The most NER deficient variant Y148D had reduced protein stability, weaker DNA binding, disrupted recruitment to damage, and degradation. Our findings demonstrate that tumor mutations in XPA impact cell survival after cisplatin treatment and provide valuable mechanistic insights to improve variant effect prediction. Broadly, these findings suggest XPA tumor variants should be considered when predicting chemotherapy response.</p>","PeriodicalId":94149,"journal":{"name":"NAR cancer","volume":"6 1","pages":"zcae013"},"PeriodicalIF":3.4,"publicationDate":"2024-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10946055/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140159805","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}
NAR cancerPub Date : 2024-03-12eCollection Date: 2024-03-01DOI: 10.1093/narcan/zcae012
Ana M Añazco-Guenkova, Borja Miguel-López, Óscar Monteagudo-García, Raquel García-Vílchez, Sandra Blanco
{"title":"The impact of tRNA modifications on translation in cancer: identifying novel therapeutic avenues.","authors":"Ana M Añazco-Guenkova, Borja Miguel-López, Óscar Monteagudo-García, Raquel García-Vílchez, Sandra Blanco","doi":"10.1093/narcan/zcae012","DOIUrl":"10.1093/narcan/zcae012","url":null,"abstract":"<p><p>Recent advancements have illuminated the critical role of RNA modifications in post-transcriptional regulation, shaping the landscape of gene expression. This review explores how tRNA modifications emerge as critical players, fine-tuning functionalities that not only maintain the fidelity of protein synthesis but also dictate gene expression and translation profiles. Highlighting their dysregulation as a common denominator in various cancers, we systematically investigate the intersection of both cytosolic and mitochondrial tRNA modifications with cancer biology. These modifications impact key processes such as cell proliferation, tumorigenesis, migration, metastasis, bioenergetics and the modulation of the tumor immune microenvironment. The recurrence of altered tRNA modification patterns across different cancer types underscores their significance in cancer development, proposing them as potential biomarkers and as actionable targets to disrupt tumorigenic processes, offering new avenues for precision medicine in the battle against cancer.</p>","PeriodicalId":94149,"journal":{"name":"NAR cancer","volume":"6 1","pages":"zcae012"},"PeriodicalIF":3.4,"publicationDate":"2024-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10928989/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140112604","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}
NAR cancerPub Date : 2024-03-12eCollection Date: 2024-03-01DOI: 10.1093/narcan/zcae011
Anouk Sesink, Margaux Becerra, Jia-Ling Ruan, Sophie Leboucher, Maxime Dubail, Sophie Heinrich, Wael Jdey, Kristoffer Petersson, Charles Fouillade, Nathalie Berthault, Marie Dutreix, Pierre-Marie Girard
{"title":"The AsiDNA™ decoy mimicking DSBs protects the normal tissue from radiation toxicity through a DNA-PK/p53/p21-dependent G1/S arrest.","authors":"Anouk Sesink, Margaux Becerra, Jia-Ling Ruan, Sophie Leboucher, Maxime Dubail, Sophie Heinrich, Wael Jdey, Kristoffer Petersson, Charles Fouillade, Nathalie Berthault, Marie Dutreix, Pierre-Marie Girard","doi":"10.1093/narcan/zcae011","DOIUrl":"10.1093/narcan/zcae011","url":null,"abstract":"<p><p>AsiDNA™, a cholesterol-coupled oligonucleotide mimicking double-stranded DNA breaks, was developed to sensitize tumour cells to radio- and chemotherapy. This drug acts as a decoy hijacking the DNA damage response. Previous studies have demonstrated that standalone AsiDNA™ administration is well tolerated with no additional adverse effects when combined with chemo- and/or radiotherapy. The lack of normal tissue complication encouraged further examination into the role of AsiDNA™ in normal cells. This research demonstrates the radioprotective properties of AsiDNA™. In vitro, AsiDNA™ induces a DNA-PK/p53/p21-dependent G1/S arrest in normal epithelial cells and fibroblasts that is absent in p53 deficient and proficient tumour cells. This cell cycle arrest improved survival after irradiation only in p53 proficient normal cells. Combined administration of AsiDNA™ with conventional radiotherapy in mouse models of late and early radiation toxicity resulted in decreased onset of lung fibrosis and increased intestinal crypt survival. Similar results were observed following FLASH radiotherapy in standalone or combined with AsiDNA™. Mechanisms comparable to those identified <i>in vitro</i> were detected both <i>in vivo</i>, in the intestine and ex vivo, in precision cut lung slices. Collectively, the results suggest that AsiDNA™ can partially protect healthy tissues from radiation toxicity by triggering a G1/S arrest in normal cells.</p>","PeriodicalId":94149,"journal":{"name":"NAR cancer","volume":"6 1","pages":"zcae011"},"PeriodicalIF":3.4,"publicationDate":"2024-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10928987/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140112552","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":"Singleton mutations in large-scale cancer genome studies: uncovering the tail of cancer genome.","authors":"Sanket Desai, Suhail Ahmad, Bhargavi Bawaskar, Sonal Rashmi, Rohit Mishra, Deepika Lakhwani, Amit Dutt","doi":"10.1093/narcan/zcae010","DOIUrl":"10.1093/narcan/zcae010","url":null,"abstract":"<p><p>Singleton or low-frequency driver mutations are challenging to identify. We present a domain driver mutation estimator (DOME) to identify rare candidate driver mutations. DOME analyzes positions analogous to known statistical hotspots and resistant mutations in combination with their functional and biochemical residue context as determined by protein structures and somatic mutation propensity within conserved PFAM domains, integrating the CADD scoring scheme. Benchmarked against seven other tools, DOME exhibited superior or comparable accuracy compared to all evaluated tools in the prediction of functional cancer drivers, with the exception of one tool. DOME identified a unique set of 32 917 high-confidence predicted driver mutations from the analysis of whole proteome missense variants within domain boundaries across 1331 genes, including 1192 noncancer gene census genes, emphasizing its unique place in cancer genome analysis. Additionally, analysis of 8799 TCGA (The Cancer Genome Atlas) and in-house tumor samples revealed 847 potential driver mutations, with mutations in tyrosine kinase members forming the dominant burden, underscoring its higher significance in cancer. Overall, DOME complements current approaches for identifying novel, low-frequency drivers and resistant mutations in personalized therapy.</p>","PeriodicalId":94149,"journal":{"name":"NAR cancer","volume":"6 1","pages":"zcae010"},"PeriodicalIF":3.4,"publicationDate":"2024-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10939354/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140133687","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}
NAR cancerPub Date : 2024-03-05eCollection Date: 2024-03-01DOI: 10.1093/narcan/zcae009
Margalida Esteva-Socias, Francesca Aguilo
{"title":"METTL3 as a master regulator of translation in cancer: mechanisms and implications.","authors":"Margalida Esteva-Socias, Francesca Aguilo","doi":"10.1093/narcan/zcae009","DOIUrl":"10.1093/narcan/zcae009","url":null,"abstract":"<p><p>Translational regulation is an important step in the control of gene expression. In cancer cells, the orchestration of both global control of protein synthesis and selective translation of specific mRNAs promote tumor cell survival, angiogenesis, transformation, invasion and metastasis. N6-methyladenosine (m<sup>6</sup>A), the most prevalent mRNA modification in higher eukaryotes, impacts protein translation. Over the past decade, the development of m<sup>6</sup>A mapping tools has facilitated comprehensive functional investigations, revealing the involvement of this chemical mark, together with its writer METTL3, in promoting the translation of both oncogenes and tumor suppressor transcripts, with the impact being context-dependent. This review aims to consolidate our current understanding of how m<sup>6</sup>A and METTL3 shape translation regulation in the realm of cancer biology. In addition, it delves into the role of cytoplasmic METTL3 in protein synthesis, operating independently of its catalytic activity. Ultimately, our goal is to provide critical insights into the interplay between m<sup>6</sup>A, METTL3 and translational regulation in cancer, offering a deeper comprehension of the mechanisms sustaining tumorigenesis.</p>","PeriodicalId":94149,"journal":{"name":"NAR cancer","volume":"6 1","pages":"zcae009"},"PeriodicalIF":3.4,"publicationDate":"2024-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10914372/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140041211","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}
NAR cancerPub Date : 2024-02-24eCollection Date: 2024-03-01DOI: 10.1093/narcan/zcae008
Jie Liu, Jing Li, Fangfang Jin, Qian Li, Guoping Zhao, Lijun Wu, Xiaoyan Li, Junfeng Xia, Na Cheng
{"title":"dbCRAF: a curated knowledgebase for regulation of radiation response in human cancer.","authors":"Jie Liu, Jing Li, Fangfang Jin, Qian Li, Guoping Zhao, Lijun Wu, Xiaoyan Li, Junfeng Xia, Na Cheng","doi":"10.1093/narcan/zcae008","DOIUrl":"10.1093/narcan/zcae008","url":null,"abstract":"<p><p>Radiation therapy (RT) is one of the primary treatment modalities of cancer, with 40-60% of cancer patients benefiting from RT during their treatment course. The intrinsic radiosensitivity or acquired radioresistance of tumor cells would affect the response to RT and clinical outcomes in patients. Thus, mining the regulatory mechanisms in tumor radiosensitivity or radioresistance that have been verified by biological experiments and computational analysis methods will enhance the overall understanding of RT. Here, we describe a comprehensive database dbCRAF (http://dbCRAF.xialab.info/) to document and annotate the factors (1,677 genes, 49 proteins and 612 radiosensitizers) linked with radiation response, including radiosensitivity, radioresistance in cancer cells and prognosis in cancer patients receiving RT. On the one hand, dbCRAF enables researchers to directly access knowledge for regulation of radiation response in human cancer buried in the vast literature. On the other hand, dbCRAF provides four flexible modules to analyze and visualize the functional relationship between these factors and clinical outcome, KEGG pathway and target genes. In conclusion, dbCRAF serves as a valuable resource for elucidating the regulatory mechanisms of radiation response in human cancers as well as for the improvement of RT options.</p>","PeriodicalId":94149,"journal":{"name":"NAR cancer","volume":"6 1","pages":"zcae008"},"PeriodicalIF":3.4,"publicationDate":"2024-02-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10894039/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139975170","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}