Neoplasia最新文献

{"title":"Ovulation sources ROS to confer mutagenic activities on the TP53 gene in the fallopian tube epithelium","authors":"Kanchana Subramani ,&nbsp;Hsuan-Shun Huang ,&nbsp;Pao-Chu Chen ,&nbsp;Dah-Ching Ding ,&nbsp;Tang-Yuan Chu","doi":"10.1016/j.neo.2024.101085","DOIUrl":"10.1016/j.neo.2024.101085","url":null,"abstract":"<div><h3>Introduction</h3><div>Epidemiological studies have implicated ovulation as a risk factor for ovarian high-grade serous carcinoma (HGSC) at the initiation stage. Precancerous lesions of HGSC commonly exhibit TP53 mutations attributed to DNA deamination and are frequently localized in the fallopian tube epithelium (FTE), a site regularly exposed to ovulatory follicular fluid (FF). This study aimed to assess the mutagenic potential of FF and investigate the expression levels and functional role of activation-induced cytidine deaminase (AID) following ovulation, along with the resulting TP53 DNA deamination.</div></div><div><h3>Methods</h3><div>The mutagenic activity of FF toward premalignant and malignant FTE cells was determined using the hypoxanthine phosphoribosyl transferase (HPRT) mutation assay with or without AID knockdown. The sequential activation of AID, including expressional induction, nuclear localization, DNA binding, and deamination, was determined. AID inducers in FF were identified, and the times of action and signaling pathways were determined.</div></div><div><h3>Results</h3><div>FF induced AID activation and <em>de novo</em> FTE cell mutagenesis in two waves of activity in accordance with post-ovulation FF exposure. The ERK-mediated early activity started at 2 min and peaked at 45 min, and the NF-κB-mediated late activity started at 6 h and peaked at 8.5 h after exposure. ROS, TNF-α, and estradiol, which are abundant in FF, all induced the two activities, while all activities were abolished by antioxidant cotreatment. AID physically bound to and biochemically deaminated the <em>TP53</em> gene, regardless of known mutational hotspots. It did not act on other prevalent tumor-suppressor genes of HGSC.</div></div><div><h3>Conclusion</h3><div>This study revealed the ROS-dependent AID-mediated mutagenic activity of the ovulatory FF. The results filled up the missing link between ovulation and the initial <em>TP53</em> mutation and invited a strategy of antioxidation in prevention of HGSC.</div></div>","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"59 ","pages":"Article 101085"},"PeriodicalIF":4.8,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11664131/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142787442","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pediatric neuro-oncology: Highlights of the last quarter-century","authors":"Phoebe Power ,&nbsp;Joelle P Straehla ,&nbsp;Jason Fangusaro ,&nbsp;Pratiti Bandopadhayay ,&nbsp;Neevika Manoharan","doi":"10.1016/j.neo.2024.101098","DOIUrl":"10.1016/j.neo.2024.101098","url":null,"abstract":"<div><div>The last quarter century has heralded dramatic changes in the field of pediatric neuro-oncology, with the era defined by profound developments in the understanding of the biological underpinnings of childhood central nervous system (CNS) tumors and translational therapeutics. Although there have been momentous strides forward in biologic, diagnostic, therapeutic, and experimental domains, considerable challenges remain and CNS tumors remain the leading cause of pediatric cancer-related mortality. Here, we review the significant advances in the field of pediatric neuro-oncology over the last 25 years and highlight ongoing hurdles facing future progress.</div></div>","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"59 ","pages":"Article 101098"},"PeriodicalIF":4.8,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11664148/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142787444","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Porcupine expression promotes the progression of oral carcinogenesis","authors":"Daniel Peña-Oyarzún ,&nbsp;Andrew F.G. Quest ,&nbsp;Lorena Lobos-González ,&nbsp;Andrea Maturana-Ramírez ,&nbsp;Montserrat Reyes","doi":"10.1016/j.neo.2024.101097","DOIUrl":"10.1016/j.neo.2024.101097","url":null,"abstract":"<div><div>Oral squamous cell carcinoma (OSCC) is the most common type of oral cancer, which is usually preceded by a potentially malignant disorder histologically diagnosed as dysplasia. We and others have provided evidence for the pro-carcinogenic role of the Wnt/β-catenin pathway in this context, in which Wnt ligands stabilize and allow relocalization of β-catenin to the nucleus for transcription of pro-survival and pro-proliferation genes. However, the contribution of Porcupine (PORCN), an O-acyltransferase that catalyzes the palmitoylation of Wnt ligands, to OSCC carcinogenesis is not known. Moreover, the effectiveness of LGK974, a novel PORCN inhibitor remains to be elucidated. By using different <em>ex vivo, in vivo</em> and <em>in vitro</em> OSCC carcinogenesis models, we show that PORCN expression is significantly increased in high-grade dysplasia as well as moderately/poorly- differentiated OSCC. Consistent with these observations, expression of key proteins involved in the Wnt/β-catenin pathway are elevated as well. Importantly, the treatment with LGK974, a chemical PORCN inhibitor, reduced the number and size of oral lesions in mice treated with 4-Nitroquinoline 1-oxide (4NQO), a tobacco smoke surrogate. These results highlight the role of PORCN during OSCC carcinogenesis.</div></div>","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"59 ","pages":"Article 101097"},"PeriodicalIF":4.8,"publicationDate":"2024-11-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142756835","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"XAF1 is secreted from stressed tumor cells to activate T cell-mediated tumor surveillance via Lck-ERK signaling","authors":"Jieun Ahn,&nbsp;Seung-Hun Jang,&nbsp;Sungchan Jang,&nbsp;Ji-Hye Yoon,&nbsp;Min-Goo Lee,&nbsp;Sung-Gil Chi","doi":"10.1016/j.neo.2024.101094","DOIUrl":"10.1016/j.neo.2024.101094","url":null,"abstract":"<div><div>X-linked inhibitor of apoptosis-associated factor 1 (XAF1) is a stress-inducible tumor suppressor that is commonly inactivated in multiple types of human malignancies. Nevertheless, the molecular basis for the XAF1-mediated tumor suppression remains largely undefined. Here, we report that XAF1 is secreted from cells under various cytotoxic stress conditions and activates T cell-mediated tumor surveillance. In cancer cells exposed to interferon <span><math><mrow><mo>−</mo><mi>γ</mi></mrow></math></span>, tumor necrosis factor <span><math><mrow><mo>−</mo><mi>α</mi></mrow></math></span>, and etoposide, XAF1 is elevated and actively secreted through the unconventional endo-lysosomal trafficking pathway and the zinc finger 4 domain of XAF1 plays an essential for this secretion. Secreted XAF1 is internalized into nearby T cells through clathrin-mediated endocytosis and stimulates proliferation, migration, and tumor infiltration of T cells. Internalized XAF1 activates RAF-MEK-ERK signaling through the direct interaction with and phosphorylation of lymphocyte-specific protein tyrosine kinase. In response to interferon <span><math><mrow><mo>−</mo><mi>γ</mi></mrow></math></span> injection, <em>Xaf1</em>^<em>+</em>^<em>/+</em> tumors display significantly higher regression rate and T cell infiltration compared to <em>Xaf1^−/−</em> tumors while <em>Xaf1</em>^−/− tumors are markedly reduced by injection of recombinant Xaf1. XAF1 expression is associated with overall survival in T cell-enriched cancer patients and also correlates with prognosis in T cell-based immunotherapies. Together, our study identifies XAF1 as a novel secretory immune-modulatory tumor suppressor, illuminating the mechanistic consequence of its inactivation in tumorigenesis.</div></div>","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"59 ","pages":"Article 101094"},"PeriodicalIF":4.8,"publicationDate":"2024-11-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142743804","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Suppression of ADP-ribosylation reversal triggers cell vulnerability to alkylating agents","authors":"Rocco Caggiano ,&nbsp;Evgeniia Prokhorova ,&nbsp;Lena Duma ,&nbsp;Kira Schützenhofer ,&nbsp;Raffaella Lauro ,&nbsp;Giuliana Catara ,&nbsp;Rosa Marina Melillo ,&nbsp;Angela Celetti ,&nbsp;Rebecca Smith ,&nbsp;S John Weroha ,&nbsp;Scott H Kaufmann ,&nbsp;Ivan Ahel ,&nbsp;Luca Palazzo","doi":"10.1016/j.neo.2024.101092","DOIUrl":"10.1016/j.neo.2024.101092","url":null,"abstract":"<div><div>The ADP-ribosyl hydrolases PARG and ARH3 counteract PARP enzymatic activity by removing ADP-ribosylation. PARG and ARH3 activities have a synthetic lethal effect; however, the specific molecular mechanisms underlying this response remain unknown. Here, we show that the PARG and ARH3 synthetic lethality is enhanced further in the presence of DNA alkylating agents, suggesting that the inability to revert ADP-ribosylation primarily affects the repair of alkylated DNA bases. <em>ARH3</em> knockout cells, treated with PARG inhibitor and alkylating genotoxins, accumulated single-stranded DNA and DNA damage, resulting in G2/M cell cycle arrest and apoptosis. Furthermore, we reveal a reduction in PARP1/PARP2 levels in <em>ARH3</em>-deficient cells treated with PARG inhibitor due to excessive ADP-ribosylation, which may contribute to alkylating agents’ vulnerability. Collectively, these results uncover the potential of targeting ADP-ribosyl hydrolases in combination with alkylating agents for cancer therapy and provide insights into the mechanisms underlying the synthetic lethal effect.</div></div>","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"59 ","pages":"Article 101092"},"PeriodicalIF":4.8,"publicationDate":"2024-11-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142743818","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"TPM4 overexpression drives colon epithelial cell tumorigenesis by suppressing differentiation and promoting proliferation","authors":"Rajsumeet S. Macwan ,&nbsp;Giulio Ferrero ,&nbsp;Barbara Pardini ,&nbsp;Alessio Naccarati ,&nbsp;Piotr B. Kozlowski ,&nbsp;Michael J. Papetti","doi":"10.1016/j.neo.2024.101093","DOIUrl":"10.1016/j.neo.2024.101093","url":null,"abstract":"<div><h3>Objective</h3><div>The high morbidity and mortality associated with colorectal cancer (CRC) and the recent increases in early-onset CRC obviate the need for novel methods to detect and treat this disease, particularly at early stages. We hypothesize that aberrant expression of genes involved in the crypt-luminal migration of colon epithelial cells, a process necessary for their growth arrest and maturation, may disrupt differentiation and transition cells from a normal to tumorigenic state.</div></div><div><h3>Methods</h3><div>We searched for contractility- and motility-related genes that are dysregulated in human CRC relative to normal colon. RNA expression of one such gene, tropomyosin 4 (<em>TPM4</em>), was measured by qRT-PCR and RNA-seq in human colorectal tissues at various stages of tumorigenesis: CRC, adenoma, and at-risk (grossly normal mucosa from a patient with Familial Adenomatous Polyposis, or FAP), relative to controls. Effects of aberrant <em>TPM4</em> expression on colon epithelial cell proliferation and maturation were determined by overexpression using stable transfection in spontaneously differentiating Caco2 cells or silencing using siRNA in proliferating cells.</div></div><div><h3>Results</h3><div><em>TPM4</em> is overexpressed at various stages of tumorigenesis, including CRC, adenoma, and grossly normal FAP colon tissue, as well as in proliferating versus differentiating Caco2 cells. <em>TPM4.2</em> overexpression in differentiating Caco2 cells markedly inhibits certain aspects of maturation, notably sucrase isomaltase and glutathione-S-transferase alpha1 expression, and causes morphological and cell junction abnormalities. Conversely, siRNA-mediated suppression of <em>TPM4.2</em> inhibits Caco2 proliferation.</div></div><div><h3>Conclusions</h3><div><em>TPM4</em> overexpression attenuates colon epithelial cell differentiation and promotes proliferation. Therefore, <em>TPM4</em> expression may be a biomarker to enhance strategies for CRC diagnosis and treatment.</div></div>","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"59 ","pages":"Article 101093"},"PeriodicalIF":4.8,"publicationDate":"2024-11-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142743805","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"5-Aza-2′-deoxycytidin (Decitabine) increases cancer-testis antigen expression in head and neck squamous cell carcinoma and modifies immune checkpoint expression, especially in CD39-positive CD8 and CD4 T cells","authors":"Adrian Fehn ,&nbsp;Adrian von Witzleben ,&nbsp;Ayla Grages ,&nbsp;Tsima Abou Kors ,&nbsp;Jasmin Ezić ,&nbsp;Annika C. Betzler ,&nbsp;Cornelia Brunner ,&nbsp;Patrick J. Schuler ,&nbsp;Marie-Nicole Theodoraki ,&nbsp;Thomas K. Hoffmann ,&nbsp;Simon Laban","doi":"10.1016/j.neo.2024.101086","DOIUrl":"10.1016/j.neo.2024.101086","url":null,"abstract":"<div><div>Failure of immunotherapy in head and neck squamous cell carcinoma (HNSCC) patients represents an unmet need to augment leverage of adaptive immunity. Immunogenic cancer-testis antigen (CTA) expression as well as lymphocyte differentiation and function are regulated by DNA methylation. Therefore, epigenetic therapy via inhibition of DNA-Methyltransferases by 5-Aza-2′-deoxycytidine (DAC) serves a promising adjuvant in immunotherapy.</div><div>We investigated the effects of DAC on CTA expression and proliferative capacity in HNSCC cell lines and on the expression of 12 immune checkpoint molecules (ICM) on lymphocytes of oropharyngeal squamous cell carcinoma (OPSCC) patients and healthy donors.</div><div>In all cell lines CTA were upregulated accompanied by decreased proliferation. In lymphocytes pronounced alterations of the ICM repertoire were observed, influenced by donor type and subpopulation. On CD39+ CD4 and CD8 T cells, the expression of co-stimulatory ICM GITR and OX40 increased dose dependently, whereas expression decreased on CD39- CD4 T cells. PD1 expression increased primarily on CD39+ CD8 T cells and decreased on CD39- CD4 T cells. CD27 expression decreased primarily in CD8 T cells, but increased in CD39- CD4 T cells, whereas ICOS expression was lowered in both CD39+ and CD39- subsets of CD4 as well as CD8 T cells.</div><div>DAC treatment increased immunogenicity and decreased proliferation in HNSCC cells while enhancing expression of co-stimulatory ICM GITR and OX40. We propose low dose DAC treatment as a adjuvant to immunotherapy.</div></div>","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"59 ","pages":"Article 101086"},"PeriodicalIF":4.8,"publicationDate":"2024-11-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142721167","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Structure and function of the lysine methyltransferase SETD2 in cancer: From histones to cytoskeleton","authors":"Christina Michail,&nbsp;Fernando Rodrigues Lima,&nbsp;Mireille Viguier,&nbsp;Frédérique Deshayes","doi":"10.1016/j.neo.2024.101090","DOIUrl":"10.1016/j.neo.2024.101090","url":null,"abstract":"<div><div>SETD2 is known to be the unique histone methyltransferase responsible for the trimethylation of the lysine 36 of histone H3 thus generating H3K36me3. This epigenetic mark is critical for transcriptional activation and elongation, DNA repair, mRNA splicing, and DNA methylation. Recurrent SETD2-inactivating mutations and altered H3K36me3 levels are found in cancer at high frequency and numerous studies indicate that SETD2 acts as a tumor suppressor. Recently, SETD2 was further shown to methylate non-histone proteins particularly the cytoskeletal proteins tubulin and actin with subsequent impacts on cytoskeleton structure, mitosis and cell migration.</div><div>Herein, we provide a review of the role of SETD2 in different cancers with special emphasis on the structural basis of the functions of this key lysine methyltransferase. Moreover, beyond the role of this enzyme in epigenetics and H3K36me3-dependent processes, we highlight the putative role of \"non-epigenetic/H3K36me3\" functions of SETD2 in cancer, particularly those involving the cytoskeleton.</div></div>","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"59 ","pages":"Article 101090"},"PeriodicalIF":4.8,"publicationDate":"2024-11-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142702719","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Early separation and parallel clonal selection of dedifferentiated and well-differentiated components in dedifferentiated liposarcoma","authors":"Tetsuya Sekita ,&nbsp;Naofumi Asano ,&nbsp;Takashi Kubo ,&nbsp;Hirohiko Totsuka ,&nbsp;Sachiyo Mitani ,&nbsp;Naoko Hattori ,&nbsp;Akihiko Yoshida ,&nbsp;Eisuke Kobayashi ,&nbsp;Motokiyo Komiyama ,&nbsp;Toshikazu Ushijima ,&nbsp;Robert Nakayama ,&nbsp;Masaya Nakamura ,&nbsp;Akira Kawai ,&nbsp;Hitoshi Ichikawa","doi":"10.1016/j.neo.2024.101074","DOIUrl":"10.1016/j.neo.2024.101074","url":null,"abstract":"<div><div>Dedifferentiated liposarcoma (DDLPS) comprises a high-grade dedifferentiated (DD) component and a juxtaposed well-differentiated (WD) component. The DD component is believed to originate from the WD component by acquiring additional genomic alterations. In this study, we performed multiregion genome, epigenome, and transcriptome analyses of three patients with DDLPS. In two patients, there were few common genomic alterations across all samples, but many common alterations within DD or WD component samples. Phylogenetic trees predicted from the genomic alterations were consistent with those predicted from DNA methylation patterns. The expression patterns of adipogenesis-related genes differed between DD and WD components and also among patients in connection with their CpG island methylation status. These results indicate that in some patients, WD and DD components are evolutionarily separated at very early stages of tumorigenesis, and are formed through relatively long clonal selection with acquisition of different driver genomic alterations and DNA methylation changes.</div></div>","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"59 ","pages":"Article 101074"},"PeriodicalIF":4.8,"publicationDate":"2024-11-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142702720","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Corrigendum to “Inhibition of Pancreatic Intraepithelial Neoplasia Progression to Carcinoma by Nitric Oxide-Releasing Aspirin in p48Cre/+-LSL-KrasG12D/+ Mice” [Neoplasia, Volume 14, Issue 9 (2012) 778-787]","authors":"Chinthalapally V Rao ,&nbsp;Altaf Mohammed ,&nbsp;Naveena B Janakiram ,&nbsp;Qian Li ,&nbsp;Rebekah L Ritchie ,&nbsp;Stan Lightfoot ,&nbsp;Awasthi Vibhudutta ,&nbsp;Vernon E Steele","doi":"10.1016/j.neo.2024.101081","DOIUrl":"10.1016/j.neo.2024.101081","url":null,"abstract":"","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"59 ","pages":"Article 101081"},"PeriodicalIF":4.8,"publicationDate":"2024-11-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142693077","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}