{"title":"Prophylactic infusion of allogeneic double-negative T cells as immune modulators to prevent relapse in high-risk AML patients post-Allo-HSCT: a phase I trial.","authors":"Guangyu Sun, Xingchi Chen, Tianzhong Pan, Kaidi Song, Haicun Xie, Meijuan Tu, Xiang Wan, Wen Yao, Yaxin Cheng, Ziwei Zhou, Dongyao Wang, Yongsheng Han, Baolin Tang, Liming Yang, Xiaoyu Zhu","doi":"10.1186/s40164-025-00680-1","DOIUrl":"10.1186/s40164-025-00680-1","url":null,"abstract":"<p><p>Relapse remains a major challenge for high-risk acute myeloid leukemia (AML) patients following allogeneic hematopoietic stem cell transplantation (allo-HSCT). In our first-in-human Phase I trial (ChiCTR-1900022795), we have demonstrated that third-party donor-derived double-negative T cells (DNTs) are safe and effective for treating relapsed AML. This Phase I study aims to further evaluate the safety and efficacy of allo-DNTs in preventing relapse in AML patients post-allo-HSCT. Six high-risk AML patients received three infusions of off-the-shelf allo-DNTs at one-month intervals, administered 60 to 100 days post-allo-HSCT without lymphodepleting chemotherapy. No dose-limiting toxicity, DNT-related graft-versus-host disease (GvHD), or severe cytokine release syndrome (CRS) occurred. With a median follow-up of 20.9 months (range: 11.4-24.6), four patients (66.7%) remained in minimal residual disease (MRD)-negative complete remission (CR), with recurrence-free survival exceeding 24 months. Patients in remission showed increased CD8⁺ and CD4⁺ T cells, total DNTs, and higher frequencies of granzyme-secreting T cells, which were absent in relapsed patients. In vitro, co-culturing AML patient CD8⁺ T cells with allo-DNTs upregulated granzyme B and interferon-γ expression, indicating CD8⁺ T cell activation. These findings suggest that allogeneic DNT immunotherapy is a safe, promising strategy to prevent relapse in high-risk AML patients post-allo-HSCT by combining intrinsic antitumor activity with immune modulation.</p>","PeriodicalId":12180,"journal":{"name":"Experimental Hematology & Oncology","volume":"14 1","pages":"90"},"PeriodicalIF":9.4,"publicationDate":"2025-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12224462/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144552741","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}
Carina Bernardo, Subhayan Chattopadhyay, Natalie Andersson, Pontus Eriksson, Benjamin Medle, Lena Tran, Nour Al Dain Marzouka, Adam Mattsson, Aymeric Zadoroznyj, Malin Larsson, Fredrik Liedberg, Mattias Höglund, Gottfrid Sjödahl
{"title":"Bladder cancer subtypes exhibit limited plasticity across different microenvironments and in metastases.","authors":"Carina Bernardo, Subhayan Chattopadhyay, Natalie Andersson, Pontus Eriksson, Benjamin Medle, Lena Tran, Nour Al Dain Marzouka, Adam Mattsson, Aymeric Zadoroznyj, Malin Larsson, Fredrik Liedberg, Mattias Höglund, Gottfrid Sjödahl","doi":"10.1186/s40164-025-00682-z","DOIUrl":"10.1186/s40164-025-00682-z","url":null,"abstract":"<p><strong>Background: </strong>Transcriptomic and genomic analyses of bladder cancer (BC) reveal a highly diverse disease stratified into molecular subtypes with distinct molecular features and biological behaviors. Intratumor heterogeneity (ITH) and plasticity can significantly impact diagnosis and patient management, yet their extent in BC remains highly debated. Here, we investigated whether the three main bladder cancer subtypes maintain or alter their identity in response to changes in the microenvironment and during metastatic colonization.</p><p><strong>Methods: </strong>Seven patient-derived xenograft (PDX) models representing the major BC subtypes were propagated into three distinct tissue microenvironments: subcutaneous, mammary fat pad and under the kidney capsule. Metastatic lesions were generated via systemic injection of tumor cells. Tumor samples were analysed using RNA- and exome sequencing, SNP-arrays and histopathology to assess subtype fidelity, genomic evolution, and clonal dynamics.</p><p><strong>Results: </strong>A comprehensive, longitudinal multiomics analysis showed that tumors consistently maintain their molecular subtype, as well as their transcriptomic and genomic profiles, across different environments. No evidence of emerging ITH or subtype transitions was observed, regardless of the microenvironment. The transcriptomic adaptations observed in metastases and different implantation sites are limited and are associated primarily with hypoxia, epithelial-mesenchymal transition (EMT), and invasion.</p><p><strong>Conclusions: </strong>Our results suggest that invasive bladder cancers have a strong intrinsic tumor identity that is not easily reprogrammed by the microenvironment.</p>","PeriodicalId":12180,"journal":{"name":"Experimental Hematology & Oncology","volume":"14 1","pages":"91"},"PeriodicalIF":9.4,"publicationDate":"2025-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12225047/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144552739","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}
Rachel M Hurley, Jill M Wagner, Arun Kanakkanthara, Annapoorna Venkatachalam, Aaron M Deisinger, Cristina Correia, Paula A Schneider, Kevin L Peterson, Elaine P Macon, Ethan P Heinzen, Kumar Sanjiv, Xiaonan Hou, Marc A Becker, Matthew J Maurer, Melissa C Larson, Elizabeth M Swisher, Hu Li, Ann L Oberg, S John Weroha, Ulrika Warpman Berglund, Thomas Helleday, Scott H Kaufmann, Andrea E Wahner Hendrickson
{"title":"Mitotic MTH1 inhibitor karonudib kills epithelial ovarian cancer independent of platinum sensitivity.","authors":"Rachel M Hurley, Jill M Wagner, Arun Kanakkanthara, Annapoorna Venkatachalam, Aaron M Deisinger, Cristina Correia, Paula A Schneider, Kevin L Peterson, Elaine P Macon, Ethan P Heinzen, Kumar Sanjiv, Xiaonan Hou, Marc A Becker, Matthew J Maurer, Melissa C Larson, Elizabeth M Swisher, Hu Li, Ann L Oberg, S John Weroha, Ulrika Warpman Berglund, Thomas Helleday, Scott H Kaufmann, Andrea E Wahner Hendrickson","doi":"10.1186/s40164-025-00681-0","DOIUrl":"10.1186/s40164-025-00681-0","url":null,"abstract":"<p><p>The prognosis for women with ovarian cancer (OC) is particularly poor if resistance to platinum compounds, the mainstay of standard-of-care therapy, develops. Inhibitors of the Nudix hydrolase MuT Homolog 1 (MTH1) have previously been shown to arrest cancer cells in mitosis, increase 8-oxo-2'-deoxyguanosine (8-oxo-dG) incorporation into DNA, and selectively kill neoplastic cells while sparing normal cells. Here we explored the cytotoxic mechanism of these agents as well as their activity against platinum-resistant OC in vitro and in vivo. Two mitotic MTH1 inhibitors (mMTH1is), TH588 and karonudib, decreased colony formation indistinguishably in platinum-sensitive OC cell lines and their platinum-resistant counterparts in vitro but had limited effects on fallopian tube and immortalized ovarian surface epithelial cells. Treatment with karonudib stalled OC cells in mitosis and caused elevated 8-oxo-dG levels in DNA followed by activation of base excision repair, induction of BAX, and apoptotic cellular demise. This cytotoxicity was blunted by overexpression of the pre-mitotic checkpoint protein CHFR, which inhibits other anti-mitotics, or treatment with the antioxidant N-acetylcysteine, which diminishes nuclear 8-oxo-dG staining, suggesting a role for both mitotic stalling and increased nuclear incorporation of oxidized nucleotides in karonudib efficacy. In three orthotopic OC patient-derived xenograft models, karonudib monotherapy induced growth delay in vivo. Moreover, addition of karonudib to carboplatin doubled median overall survival in two models and prolonged survival for the duration of the study (110 days) in the third. These results demonstrate activity of mMTH1is as monotherapy and in combination with carboplatin in OC that warrants further investigation.</p>","PeriodicalId":12180,"journal":{"name":"Experimental Hematology & Oncology","volume":"14 1","pages":"88"},"PeriodicalIF":13.5,"publicationDate":"2025-06-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12183885/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144474393","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}
Jaewoo Park, Min Sung Joo, Myung Jun Kim, Seungseok Oh, Phuong Thao Tran, Minju Kwon, Yong June Choi, JaeYung Lee, Eun-Jung Kim, Dong Hyuk Ki, Hunmi Choi, Wooseok Han, Keon Wook Kang
{"title":"High cereblon expression in neuroendocrine cancer confers vulnerability to GSPT1 molecular glue degrader.","authors":"Jaewoo Park, Min Sung Joo, Myung Jun Kim, Seungseok Oh, Phuong Thao Tran, Minju Kwon, Yong June Choi, JaeYung Lee, Eun-Jung Kim, Dong Hyuk Ki, Hunmi Choi, Wooseok Han, Keon Wook Kang","doi":"10.1186/s40164-025-00674-z","DOIUrl":"10.1186/s40164-025-00674-z","url":null,"abstract":"<p><strong>Background: </strong>Recent advances in targeted therapies have introduced molecular glue degraders (MGDs) that leverage the cereblon (CRBN) E3 ubiquitin ligase to degrade the translation termination factor GSPT1. Understanding the cellular context for the selective targeting of cancer cells by GSPT1 MGDs is crucial.</p><p><strong>Methods: </strong>This study investigated the sensitivity of neuroendocrine cancer (NEC) cells to GSPT1MGDs across a pan-cancer cell line panel, examining the correlation between therapeutic response and cellular characteristics such as CRBN expression and neuroendocrine (NE) marker levels. The role of CRBN in enhancing MGD sensitivity was further validated through CRBN overexpression and NEC-driving factor expression experiments in non-NEC and lung adenocarcinoma cells. The sensitivity of acute myeloid leukemia (AML) cells, which share transcriptomic features with NECs, to GSPT1 MGDs was also evaluated.</p><p><strong>Results: </strong>NEC cells with high CRBN expression exhibited marked sensitivity to GSPT1 MGDs compared to other cancer types. GSPT1 degradation was more rapid and robust in NEC cells, highlighting the cellular context dependency of the treatment. A strong correlation was observed between CRBN expression and NE characteristics, whereas no such correlation was found with GSPT1 expression. CRBN overexpression in non-NEC cells significantly increased their sensitivity to GSPT1 MGDs, as did the ectopic expression of NEC-driving factors, which upregulated CRBN levels in lung adenocarcinoma cells. Additionally, AML cells, with high CRBN expression, showed similar sensitivity to GSPT1 MGDs, mirroring the behavior of NECs.</p><p><strong>Conclusions: </strong>CRBN expression is a critical determinant of the selective cytotoxicity of GSPT1 MGDs in NECs and other cancers with shared transcriptomic features, such as AML. These findings underscore the therapeutic potential of targeting NECs using GSPT1 MGDs, paving the way for a more refined and selective approach in treating aggressive cancers.</p>","PeriodicalId":12180,"journal":{"name":"Experimental Hematology & Oncology","volume":"14 1","pages":"89"},"PeriodicalIF":9.4,"publicationDate":"2025-06-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12186427/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144474392","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}
Mengyue Lei, Jessica Gai, Thomas J McPhaul, Huijuan Luo, Penghui Lin, Dongbing Liu, Michael Pishvaian, Nicholas J Roberts, Kui Wu, Jin He, Lei Zheng
{"title":"Homologous recombination-DNA damage response defects increase TMB and neoantigen load, but not effector T cell density and clonal diversity in pancreatic cancer.","authors":"Mengyue Lei, Jessica Gai, Thomas J McPhaul, Huijuan Luo, Penghui Lin, Dongbing Liu, Michael Pishvaian, Nicholas J Roberts, Kui Wu, Jin He, Lei Zheng","doi":"10.1186/s40164-025-00673-0","DOIUrl":"10.1186/s40164-025-00673-0","url":null,"abstract":"<p><p>Pancreatic ductal adenocarcinoma (PDAC) is highly resistant to chemotherapy. However, PDAC with germline BRCA mutations, which lead to homologous recombination (HR) deficiency (HRD), demonstrated an increased sensitivity to platinum-based chemotherapy regimens. This increased chemosensitivity was also seen in PDACs with germline or somatic mutations in the DNA double-strand damage response (DDR) genes beyond canonical HR genes such as BRCA1, BRCA2, and PALB2. However, there are no consensus methods to determine HRD status; and neither is there a well-defined list of HR-DDR genes. In addition, how HRD and/or HR-DDR gene mutation status impacts the tumor immune microenvironment including tumor mutation burden (TMB), neoantigen load, T cell receptor (TCR) repertoire, and effector T cell infiltration is unknown. Thus, in this study, we developed a new method to categorize PDACs into HRD-positive and HRD-negative subgroups by using results from whole exome sequencing, whole genome sequencing, or both into consideration. We classified a cohort of 89 PDACs into HRD-positive (n = 18) and HRD-negative (n = 69) tumors. HR-DDR gene variants were identified more frequently in HRD-positive PDACs than HRD-negative PDACs, with RAD51B, BRCA2 and ATM alterations most frequently identified in HRD-positive PDACs. Notably, TMB and neoantigen load was significantly higher in HRD-positive PDACs compared to HRD-negative tumors. Interestingly, HRD-positive PDACs, PDACs with high tumor mutational burden, and PDAC with high neoantigen load were all associated with lower CD8 + T lymphocyte infiltration and T cell clonal diversity, suggesting a mechanism of resistance to immune checkpoint inhibitors (ICIs). Therefore, this study suggests that treatments to enhance effector T cell infiltration and T cell clonal diversity may overcome resistance to ICI-based immunotherapy in HRD-positive PDACs.</p>","PeriodicalId":12180,"journal":{"name":"Experimental Hematology & Oncology","volume":"14 1","pages":"86"},"PeriodicalIF":9.4,"publicationDate":"2025-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12178057/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144324897","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}
Rohit Thalla, Ryan Mack, Jorgena Kosti-Schwartz, Peter Breslin, Jiwang Zhang
{"title":"Advances and challenges in the treatment of myelodysplastic syndromes.","authors":"Rohit Thalla, Ryan Mack, Jorgena Kosti-Schwartz, Peter Breslin, Jiwang Zhang","doi":"10.1186/s40164-025-00678-9","DOIUrl":"10.1186/s40164-025-00678-9","url":null,"abstract":"<p><p>Myelodysplastic syndromes (MDS) is a heterogeneous group of pre-leukemic diseases characterized by peripheral blood cytopenia, morphologic dysplasia, and an increased risk of transformation to leukemia. MDS develop from genetically mutant clonal hematopoietic stem and progenitor cells (HSPCs) which have defects in generating mature functional blood cells due to impaired differentiation and/or survival activities. In addition, mutant HSPCs also inhibit the generation of new blood cells from remaining healthy HSPCs. Thus, the complete elimination of mutant HSPCs is the optimal goal for MDS treatment. However, most current therapies for MDS are little more than palliative, primarily addressing cytopenia-related symptoms and improving the quality of life. Only the hypomethylating agents (HMA) lenalidomide and imetelstat reduced the mutational burden, and then only in a small subset of cases. Many HMA-based combination therapies failed to show benefits superior to single-agent HMA treatment in clinical trials. At the present time, allogeneic hematopoietic stem cell transplantation (allo-HSCT) is still the only cure for the minority of qualified patients who have HLA-matched donors. Novel effective treatments are urgently needed. Here we summarize the current standard therapeutic approaches for MDS patients and discuss major advances in MDS research and treatments. We also discuss major challenges and potential solutions to overcome these challenges for future MDS research and drug development.</p>","PeriodicalId":12180,"journal":{"name":"Experimental Hematology & Oncology","volume":"14 1","pages":"87"},"PeriodicalIF":9.4,"publicationDate":"2025-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12177969/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144324896","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}
Yuhui Tang, Aiqi Xu, Zhongbiao Xu, Jindong Xie, Wei Huang, Liulu Zhang, Yitian Chen, Lu Yang, Shasha Du, Kun Wang
{"title":"Multi-omics analyses of the heterogenous immune microenvironment in triple-negative breast cancer implicate UQCRFS1 potentiates tumor progression.","authors":"Yuhui Tang, Aiqi Xu, Zhongbiao Xu, Jindong Xie, Wei Huang, Liulu Zhang, Yitian Chen, Lu Yang, Shasha Du, Kun Wang","doi":"10.1186/s40164-025-00672-1","DOIUrl":"10.1186/s40164-025-00672-1","url":null,"abstract":"<p><strong>Background: </strong>Triple-negative breast cancer (TNBC) is commonly characterized by high-grade and aggressive features, resulting in an augmented likelihood of distant metastasis and inferior prognosis for patients. Tumor immune microenvironment (TME) has been recently considered to be tightly correlated with tumor progression and immunotherapy response. However, the actual heterogenous TME within TNBC remains more explorations.</p><p><strong>Methods: </strong>The thorough analyses of different cell types within TME were conducted on the self-tested single-cell RNA sequencing dataset which contained nine TNBC treatment-naïve patients, including subclusters classification, CellChat algorithm, transcription factors (TFs) expression, pseudotime analysis and functional enrichment assay. The malignant epithelial cluster was confirmed by copy number variations analysis, and subsequently LASSO-Cox regression was carried out to establish a Malignant Cell Index (MCI) model on the basis of five crucial genes (BGN, SDC1, IMPDH2, SPINT1, and UQCRFS1), which was validated in several TNBC cohorts through Kaplan-Meier survival and immunotherapy response analyses. The public spatial transcriptome, proteome data and qRT-PCR, western blotting experiments were exploited to corroborate UQCRFS1 expression in RNA and protein levels. Additionally, functional experiments were implemented to unravel the impacts of UQCRFS1 on TNBC cells.</p><p><strong>Results: </strong>The diverse subclusters of TME cells within TNBC were clarified to display distinct characteristics in cell-cell interactions, TFs expression, differentiation trajectory and functional pathways. Particularly, IL32<sup>high</sup> Treg imparted an essential effect on tumor evasion and predicted a worsened prognosis of TNBC patients. Furthermore, MCI model enabled to notify the inferior prognosis and immunotherapy resistance in TNBC. Ultimately, UQCRFS1 knockdown dampened the proliferative and migratory competence in vitro as well as tumor growth in vivo of TNBC cells.</p><p><strong>Conclusions: </strong>Our study offers innovative perspectives on comprehending the heterogeneity within TME of TNBC, thereby facilitating the elucidation of TNBC biology and providing clinical recommendations for TNBC patients' prognosis, such as IL32<sup>high</sup> Treg infiltration, MCI evaluation, and UQCRFS1 expression.</p>","PeriodicalId":12180,"journal":{"name":"Experimental Hematology & Oncology","volume":"14 1","pages":"85"},"PeriodicalIF":9.4,"publicationDate":"2025-06-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12172350/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144309734","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":"Platelets in cancer and immunotherapy: functional dynamics and therapeutic opportunities.","authors":"Changjing Cai, Yiting Liu, Ruohuang Lu, Xudong Fan, Shan Zeng, Pingping Gan","doi":"10.1186/s40164-025-00676-x","DOIUrl":"10.1186/s40164-025-00676-x","url":null,"abstract":"<p><p>Platelets play a critical role in tumor immunity, particularly in promoting cancer progression. Numerous studies suggest that platelets could serve as a novel target for cancer immunotherapy, however, no comprehensive reviews have yet summarized and discussed this potential. Our review provides an in-depth discussion of the roles and mechanisms of platelets within both the immunosuppressive tumor microenvironment and the anti-tumor immune microenvironment. Additionally, we summarize the key therapeutic targets and approaches for clinical translation. This work offers essential insights for reprogramming platelets to shift their function from tumor promotion to tumor suppression, providing a foundation for the development of novel immunotherapeutic strategies and related research.</p>","PeriodicalId":12180,"journal":{"name":"Experimental Hematology & Oncology","volume":"14 1","pages":"83"},"PeriodicalIF":9.4,"publicationDate":"2025-06-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12166581/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144293606","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}