Cancer Cell International最新文献

{"title":"Complicated role of ALKBH5 in gastrointestinal cancer: an updated review.","authors":"Weitong Shu, Qianying Huang, Rui Chen, Huatao Lan, Luxin Yu, Kai Cui, Wanjun He, Songshan Zhu, Mei Chen, Li Li, Dan Jiang, Guangxian Xu","doi":"10.1186/s12935-024-03480-5","DOIUrl":"10.1186/s12935-024-03480-5","url":null,"abstract":"<p><p>Gastrointestinal cancer is the most common malignancy in humans, often accompanied by poor prognosis. N6-methyladenosine (m6A) modification is widely present in eukaryotic cells as the most abundant RNA modification. It plays a crucial role in RNA splicing and processing, nuclear export, translation, and stability. Human AlkB homolog 5 (ALKBH5) is a type of RNA demethylase exhibiting abnormal expression in various gastrointestinal cancers.It is closely related to the tumorigenesis, proliferation, migration, and other biological functions of gastrointestinal cancer. However, recent studies indicated that the role and mechanism of ALKBH5 in gastrointestinal cancer are complicated and even controversial. Thus, this review summarizes recent advances in elucidating the role of ALKBH5 as a tumor suppressor or promoter in gastrointestinal cancer. It examines the biological functions of ALKBH5 and its potential as a therapeutic target, providing new perspectives and insights for gastrointestinal cancer research.</p>","PeriodicalId":9385,"journal":{"name":"Cancer Cell International","volume":"24 1","pages":"298"},"PeriodicalIF":5.3,"publicationDate":"2024-08-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11344947/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142055039","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":"Characterization of the stem cell landscape and identification of a stemness-associated prognostic signature in bladder cancer.","authors":"Gaoteng Lin, Jiamei Lin, Hao Wang, Liucheng Wang, Fangfang Zhan, Liqian Wu, Liang Xue, Yang Dong, Wanqing Wei, Lin Liu","doi":"10.1186/s12935-024-03465-4","DOIUrl":"10.1186/s12935-024-03465-4","url":null,"abstract":"<p><p>It is accepted that cancer stem cells (CSCs) are key to the occurrence, progression, drug resistance, and recurrence of bladder cancer (BLCA). Here, we aimed to characterize the landscapes of CSCs and investigate the biological and clinical signatures based on a prognostic model constructed by genes associated with CSCs. The malignant epithelial cells were discovered and sorted into six clusters through single cell analysis. C2 was identified as the CSCs. The signaling involved in the interactions between C2, cancer-associated fibroblasts (CAFs), and immune cells mainly consisted of MK, THBS, ANGPTL, VISFATIN, JAM, and ncWNT pathways. The CSC-like prognostic index (CSCLPI) constructed by the random survival forest was a reliable risk factor for BLCA and had a stable and powerful effect on predicting the overall survival of patients with BLCA. The level of CAFs was higher among patients with higher CSCLPI scores, suggesting that CAFs play a significant role in regulating biological characteristics. The CSCLPI-developed survival prediction nomogram has the potential to be applied clinically to predict the 1-, 2-, 3-, and 5-year overall survival of patients with BLCA. The CSCLPI can be used for prognostic prediction and drug treatment evaluation in the clinic.</p>","PeriodicalId":9385,"journal":{"name":"Cancer Cell International","volume":"24 1","pages":"299"},"PeriodicalIF":5.3,"publicationDate":"2024-08-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11344935/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142055038","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":"Prognostic and immunological implications of heterogeneous cell death patterns in prostate cancer.","authors":"Ming Wang, Bangshun Dai, Qiushi Liu, Xiansheng Zhang","doi":"10.1186/s12935-024-03462-7","DOIUrl":"10.1186/s12935-024-03462-7","url":null,"abstract":"<p><strong>Background: </strong>Prostate cancer is one of the most common cancers in men with a significant proportion of patients developing biochemical recurrence (BCR) after treatment. Programmed cell death (PCD) mechanisms are known to play critical roles in tumor progression and can potentially serve as prognostic and therapeutic biomarkers in PCa. This study aimed to develop a prognostic signature for BCR in PCa using PCD-related genes.</p><p><strong>Materials and methods: </strong>We conducted an analysis of 19 different modes of PCD to develop a comprehensive model. Bulk transcriptomic, single-cell transcriptomic, genomic, and clinical data were collected from multiple cohorts, including TCGA-PRAD, GSE58812, METABRIC, GSE21653, and GSE193337. We analyzed the expression and mutations of the 19 PCD modes and constructed, evaluated, and validated the model.</p><p><strong>Results: </strong>Ten PCD modes were found to be associated with BCR in PCa, with specific PCD patterns exhibited by various cell components within the tumor microenvironment. Through Lasso Cox regression analysis, we established a Programmed Cell Death Index (PCDI) utilizing an 11-gene signature. High PCDI values were validated in five independent datasets and were found to be associated with an increased risk of BCR in PCa patients. Notably, older age and advanced T and N staging were associated with higher PCDI values. By combining PCDI with T staging, we constructed a nomogram with enhanced predictive performance. Additionally, high PCDI values were significantly correlated with decreased drug sensitivity, including drugs such as Docetaxel and Methotrexate. Patients with lower PCDI values demonstrated higher immunophenoscores (IPS), suggesting a potentially higher response rate to immune therapy. Furthermore, PCDI was associated with immune checkpoint genes and key components of the tumor microenvironment, including macrophages, T cells, and NK cells. Finally, clinical specimens validated the differential expression of PCDI-related PCDRGs at both the gene and protein levels.</p><p><strong>Conclusion: </strong>In conclusion, we developed a novel PCD-based prognostic feature that successfully predicted BCR in PCa patients and provided insights into drug sensitivity and potential response to immune therapy. These findings have significant clinical implications for the treatment of PCa.</p>","PeriodicalId":9385,"journal":{"name":"Cancer Cell International","volume":"24 1","pages":"297"},"PeriodicalIF":5.3,"publicationDate":"2024-08-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11344416/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142055040","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":"Extracellular vesicle-bound VEGF in oral squamous cell carcinoma and its role in resistance to Bevacizumab Therapy.","authors":"Jiasheng Zhou, Xue Liu, Qi Dong, Jiao Li, Weidong Niu, Tingjiao Liu","doi":"10.1186/s12935-024-03476-1","DOIUrl":"10.1186/s12935-024-03476-1","url":null,"abstract":"<p><strong>Background: </strong>Vascular endothelial growth factor (VEGF) is an important proangiogenic factor and has been considered as a key target of antiangiogenetic therapy in oral squamous cell carcinoma (OSCC). However, clinical application of bevacizumab, a specific VEGF antibody, didn't improve the survival rate of OSCC patients. One possible explanation is that VEGF gene expresses diverse isoforms, which associate with extracellular vesicles (EVs), and EVs potentially contribute to VEGF resistance to bevacizumab. However, clear solution is lacking in addressing this issue.</p><p><strong>Methods: </strong>Expression of VEGF isoforms in OSCC cells was confirmed by reverse transcription and polymerase chain reaction (RT-PCR) and western blot. EVs isolated from OSCC cell's conditioned medium (CM) were characterized by western blot, transmission electron microscopy (TEM) and nanoparticle tracking analysis (NTA). Flow cytometry, immunogold labeling and western blot were applied to study the VEGF on EVs. Tube formation assay and Matrigel plug angiogenesis assay were used for analyzing the angiogenesis capacity of EV-VEGF.</p><p><strong>Results: </strong>The most popular isoforms expressed by VEGF gene are VEGF₁₂₁, VEGF₁₆₅ and VEGF₁₈₉. In this study, we demonstrated that all three isoforms of mRNA could be detected at varying levels in OSCC cells, while only VEGF₁₆₅ and VEGF₁₈₉ proteins were found. CM derived from OSCC cells, both soluble and non-soluble forms of VEGF could be detected. We further confirmed the presence of VGEF₁₈₉ bound to EVs as a non-soluble form. EV-bound VEGF₁₈₉ presented angiogenic activity, which could not be neutralized by bevacizumab. It was found that VEGF₁₈₉ bound to EVs by heparan sulfate proteoglycans (HSPG). In addition, the angiogenic effect of EV-VEGF could be reversed by surfen, a kind of HSPG antagonist both in vitro and in vivo.</p><p><strong>Conclusion: </strong>Antagonists targeting HSPG might potentially overcome the resistance of EV-VEGF to bevacizumab and serve as an alternative for anti-VEGF therapy in OSCC.</p>","PeriodicalId":9385,"journal":{"name":"Cancer Cell International","volume":"24 1","pages":"296"},"PeriodicalIF":5.3,"publicationDate":"2024-08-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11344308/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142046407","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":"Lipid metabolism associated crosstalk: the bidirectional interaction between cancer cells and immune/stromal cells within the tumor microenvironment for prognostic insight.","authors":"Zhongshu Lin, Guanxiang Hua, Xiaojuan Hu","doi":"10.1186/s12935-024-03481-4","DOIUrl":"10.1186/s12935-024-03481-4","url":null,"abstract":"<p><p>Cancer is closely related to lipid metabolism, with the tumor microenvironment (TME) containing numerous lipid metabolic interactions. Cancer cells can bidirectionally interact with immune and stromal cells, the major components of the TME. This interaction is primarily mediated by fatty acids (FAs), cholesterol, and phospholipids. These interactions can lead to various physiological changes, including immune suppression, cancer cell proliferation, dissemination, and anti-apoptotic effects on cancer cells. The physiological modulation resulting from this lipid metabolism-associated crosstalk between cancer cells and immune/stromal cells provides valuable insights into cancer prognosis. A comprehensive literature review was conducted to examine the function of the bidirectional lipid metabolism interactions between cancer cells and immune/stromal cells within the TME, particularly how these interactions influence cancer prognosis. A novel autophagy-extracellular vesicle (EV) pathway has been proposed as a mediator of lipid metabolism interactions between cancer cells and immune cells/stromal cells, impacting cancer prognosis. As a result, different forms of lipid metabolism interactions have been described as being linked to cancer prognosis, including those mediated by the autophagy-EV pathway. In conclusion, understanding the bidirectional lipid metabolism interactions between cancer cells and stromal/immune cells in the TME can help develop more advanced prognostic approaches for cancer patients.</p>","PeriodicalId":9385,"journal":{"name":"Cancer Cell International","volume":"24 1","pages":"295"},"PeriodicalIF":5.3,"publicationDate":"2024-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11342506/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142035330","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":"Telomerase related molecular subtype and risk model reveal immune activity and evaluate prognosis and immunotherapy response in prostate cancer.","authors":"Dongze Liu, Zheng Qin, Bocun Yi, Hongbo Xie, Yunan Liang, Liang Zhu, Kuo Yang, Yong Xu, Hongtuan Zhang","doi":"10.1186/s12935-024-03477-0","DOIUrl":"10.1186/s12935-024-03477-0","url":null,"abstract":"<p><strong>Background: </strong>Prostate cancer ranks among the six most lethal malignancies worldwide. Telomerase, a reverse transcriptase enzyme, plays a pivotal role in extending cellular telomeres and is intimately associated with cell proliferation and division. However, the interconnection between prostate cancer and telomerase-related genes (TEASEs) remains unclear.</p><p><strong>Methods: </strong>Somatic mutations and copy number alterations of TEASEs were comprehensively analyzed. Subsequently, the transcripts of prostate cancer patients in TCGA and GEO databases were integrated to delineate new molecular subtypes. Followed by constructing a risk model containing nine characteristic genes through Lasso regression and Cox prognostic analysis among different subtypes. Various aspects including prognosis, tumor microenvironment (TME), landscape of immunity, tumor mutational burden (TMB), stem cell correlation, and median inhibitory concentration amongst different risk groups were compared. Finally, the expression, prognosis, and malignant biological behavior of ZW10 interactor (ZWINT) in vitro was explored.</p><p><strong>Results: </strong>TEASEs exhibited a notably high mutation frequency. Three distinct molecular subtypes and two gene subclusters based on TEASEs were delineated, displaying significant associations with prognosis, immune function regulation, and clinical characteristics. Low-risk patients demonstrated superior prognosis and better response to immunotherapy. Conversely, high-risk patients exhibited higher TMB and stronger stem cell correlations. It was also found that the patients' sensitivity to chemotherapy agents was impacted by the risk score. Finally, ZWINT's potential as a novel diagnostic and prognostic biomarker for prostate cancer was validated.</p><p><strong>Conclusions: </strong>TEASEs play a pivotal role in modulating immune regulation and immunotherapeutic responses, thereby significantly impacting the diagnosis, prognosis, and treatment strategies for affected patients.</p>","PeriodicalId":9385,"journal":{"name":"Cancer Cell International","volume":"24 1","pages":"294"},"PeriodicalIF":5.3,"publicationDate":"2024-08-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11330135/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141995358","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":"Correction: AAA237, an SKP2 inhibitor, suppresses glioblastoma by inducing BNIP3-dependent autophagy through the mTOR pathway.","authors":"Yizhi Zhang, Wan Li, Yihui Yang, Sen Zhang, Hong Yang, Yue Hao, Xu Fang, Guanhua Du, Jianyou Shi, Lianqiu Wu, Jinhua Wang","doi":"10.1186/s12935-024-03473-4","DOIUrl":"10.1186/s12935-024-03473-4","url":null,"abstract":"","PeriodicalId":9385,"journal":{"name":"Cancer Cell International","volume":"24 1","pages":"293"},"PeriodicalIF":5.3,"publicationDate":"2024-08-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11329994/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141995402","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":"Sensitization of hepatocellular carcinoma cells to HDACi is regulated through hsa-miR-342-5p/CFL1.","authors":"Parvathi Nakka, Chikondi Jassi, Ming-Cheng Chen, Yi-Sheng Liu, Jer-Yuh Liu, Chung-Min Yeh, Chi-Cheng Li, Yu-Chun Chang, Wei-Wen Kuo, Chih-Yang Huang","doi":"10.1186/s12935-024-03450-x","DOIUrl":"10.1186/s12935-024-03450-x","url":null,"abstract":"<p><strong>Background: </strong>Increased prevalence of hepatocellular carcinoma (HCC) remains a global health challenge. HCC chemoresistance is a clinical obstacle for its management. Aberrant miRNA expression is a hallmark for both cancer progression and drug resistance. However, it is unclear which miRNAs are involved in HCC chemoresistance.</p><p><strong>Methods: </strong>MicroRNA microarray analysis revealed a differential expression profile of microRNAs between the hepatocellular carcinoma HA22T cell line and the HDACi-R cell line, which was validated by quantitative real-time PCR (qRT-PCR). To determine the biological function of miR-342-5p and the mechanism of the microRNA-342-5p/CFL1 axis in hepatocellular carcinoma HDACi resistance, loss- and gain-of-function studies were conducted in vitro.</p><p><strong>Results: </strong>Here we demonstrated the molecular mechanism of histone deacetylase inhibitor (HDACi) resistance in HCC. Differential miRNA expression analysis showed significant down regulation of miR-342-5p in HDACi-R cells than in parental HA22T cells. Mimics of miR-342-5p enhanced apoptosis through upregulation of Bax, cyto-C, cleaved-caspase-3 expressions with concomitant decline in anti-apoptotic protein (Bcl-2) in HDACi-R cells. Although HDACi did not increase cell viability of HDACi-R, overexpression of miR-342-5p decreased cofilin-1 expression, upregulated reactive oxygen species (ROS) mediated apoptosis, and sensitized HDACi-R to HDACi in a dose-dependent manner.</p><p><strong>Conclusion: </strong>Our findings demonstrated the critical role of miR-342-5p in HDACi resistance of HCC and that this mechanism might be attributed to miR-342-5p/cofilin-1 regulation.</p>","PeriodicalId":9385,"journal":{"name":"Cancer Cell International","volume":"24 1","pages":"291"},"PeriodicalIF":5.3,"publicationDate":"2024-08-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11328471/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141995357","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":"Correction: ARAP1-AS1: A novel long non-coding RNA with a vital regulatory role in human cancer development.","authors":"Jialing Wang, Hongliang Luo, Lu Yang, Huazhao Yuan","doi":"10.1186/s12935-024-03475-2","DOIUrl":"10.1186/s12935-024-03475-2","url":null,"abstract":"","PeriodicalId":9385,"journal":{"name":"Cancer Cell International","volume":"24 1","pages":"292"},"PeriodicalIF":5.3,"publicationDate":"2024-08-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11328365/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141995356","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":"Does rAj-Tspin, a novel peptide from A. japonicus, exert antihepatocellular carcinoma effects via the ITGB1/ZYX/FAK/AKT signaling pathway?","authors":"Ying Che, Xiaolong Lu, Xueting Wang, Zhien Liu, Liyang Guan, Xin Li, Zaixing Du, Hang Ren, Jihong Wang, Zunchun Zhou, Li Lv","doi":"10.1186/s12935-024-03468-1","DOIUrl":"10.1186/s12935-024-03468-1","url":null,"abstract":"<p><p>rAj-Tspin, a soluble recombinant peptide from Apostichopus japonicus, can inhibit the integrin β1 (ITGB1)/FAK/AKT signaling pathway in hepatocellular carcinoma (HCC) via cell epithelial-mesenchymal transition (EMT) and apoptosis. Zyxin (ZYX) is a focal adhesion protein that is considered a novel mediator of EMT and apoptosis. However, the inhibitory mechanisms of rAj-Tspin in HCC and whether it is related to ZYX are unclear. We examined the antitumor effect of rAj-Tspin on the Huh7 human HCC cell line and on a nude mouse model generated via subcutaneous injection or orthotopic intrahepatic transplantation of Huh7 cells. Our results revealed that rAj-Tspin strikingly reduced the viability and promoted the apoptosis of Huh7 cells and inhibited HCC tumor growth in nude mice. rAj-Tspin inhibited ITGB1 and ZYX protein expression in vivo and in vitro in a dose-dependent manner. Mechanistically, the FAK/AKT signaling pathway and the proliferation and invasion of HCC cells were suppressed upon ITGB1 and ZYX knockdown. Moreover, the effect of ITGB1 overexpression on the growth of HCC cells was inhibited by rAj-Tspin. In contrast, the promoting effect of ITGB1 overexpression could be inhibited by ZYX knockdown. ZYX knockdown had no effect on ITGB1 expression. These findings suggest that ZYX is required for the indispensable role of ITGB1 in rAj-Tspin-alleviated HCC and provide an important therapeutic target for HCC. In summary, the anti-HCC effect of rAj-Tspin potentially involves the regulation of the ITGB1/ZYX/FAK/AKT pathway, which in turn impacts EMT and apoptosis.</p>","PeriodicalId":9385,"journal":{"name":"Cancer Cell International","volume":"24 1","pages":"290"},"PeriodicalIF":5.3,"publicationDate":"2024-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11325833/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141981694","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}