Blood Cancer Discovery最新文献

{"title":"Molecular Plasticity Results in Oncofetal Reprogramming and Therapeutic Vulnerabilities in Juvenile Myelomonocytic Leukemia.","authors":"Mark Hartmann, Maximilian Schönung, Jovana Rajak, Valentin Maurer, Ling Hai, Katharina Bauer, Mariam Hakobyan, Sina Stäble, Jens Langstein, Laura Jardine, Roland Roelz, Sheila Bohler, Eleonora Khabirova, Abdul-Habib Maag, Dominik Vonficht, Dirk Lebrecht, Kathrin M Bernt, Kai Tan, Changya Chen, Fatemeh Alikarami, Julia Meyer, Jun Wang, Tobias Boch, Viktoria Flore, Pavlo Lutsik, Michael D Milsom, Simon Raffel, Christian Buske, Simon Haas, Muzlifah Haniffa, Jan-Philipp Mallm, Sam Behjati, Marc-Jan Bonder, Stefan Fröhling, Elliot Stieglitz, Charlotte M Niemeyer, Joschka Hey, Christian Flotho, Christoph Plass, Miriam Erlacher, Matthias Schlesner, Daniel B Lipka","doi":"10.1158/2643-3230.BCD-25-0246","DOIUrl":"10.1158/2643-3230.BCD-25-0246","url":null,"abstract":"<p><p>Persistent fetal gene expression in childhood neoplasms is usually explained by a maturation block originating in the prenatal phase. In contrast, reactivation of fetal genes in adult malignancies is considered a consequence of oncofetal reprogramming (OFR) and is associated with aggressive disease. By reconstructing epigenetic ontogeny in juvenile myelomonocytic leukemia (JMML), we identified a postnatal maturation state of JMML stem cells with high transcriptional plasticity indicative of OFR in high-risk disease. Similarly, postnatal activation of oncogenic signaling by inducible Ptpn11E76K mutation in mice triggered molecular plasticity and reactivation of fetal gene expression. Integrative multi-omics analysis revealed aberrant CD52 expression as a feature of high-risk JMML stem cells. Anti-CD52 treatment depleted JMML stem cells and blocked disease propagation in xenograft models. Our results challenge the prevailing maturation block model of pediatric leukemogenesis and establish RAS-associated stem cell plasticity as a determinant of OFR and potential therapeutic vulnerabilities in high-risk JMML.</p><p><strong>Significance: </strong>Persistent fetal gene expression in pediatric malignancies is considered a consequence of prenatal maturation blockade. In this study, we demonstrate that oncogenic PTPN11 mutations enhance cellular plasticity. This leads to partial restoration of fetal molecular programs, creating new therapeutically exploitable vulnerabilities. See related commentary by Miao and Xu, pp. 168.</p>","PeriodicalId":29944,"journal":{"name":"Blood Cancer Discovery","volume":" ","pages":"306-330"},"PeriodicalIF":12.2,"publicationDate":"2026-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145688303","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Remodeling of Mitochondrial Networks: Cellular Adaptation and Microenvironmental Reprogramming in Hematologic Malignancies.","authors":"Yutang Li, Xinting Hu, Xiangxiang Zhou","doi":"10.1158/2643-3230.BCD-25-0338","DOIUrl":"10.1158/2643-3230.BCD-25-0338","url":null,"abstract":"<p><p>Mitochondria regulate critical cellular processes beyond energy production, including organelle quality control, programmed cell death, and intercellular and interorganellar communication. In hematologic malignancies, mitochondria undergo adaptations through mechanisms including genetic mutations, metabolic reprogramming, mitochondrial transfer, fusion, and mitophagy. These alterations create heterogeneity, contribute to therapeutic resistance, and can also reshape the tumor microenvironment to promote progression. Collectively, these findings suggest that mitochondria represent a promising frontier in next-generation therapeutics, with emerging strategies such as mitochondrial-targeted small molecules and mitochondrial transplantation holding significant therapeutic potential.</p><p><strong>Significance: </strong>In this review, we summarize the functions of mitochondria beyond energy production and highlight the heterogeneity of mitochondrial functional adaptations in hematologic malignancies, as well as the vital role of mitochondrial alterations in reshaping the tumor microenvironment. Understanding these changes is critical to deciphering the pathophysiology of hematologic malignancies.</p>","PeriodicalId":29944,"journal":{"name":"Blood Cancer Discovery","volume":" ","pages":"212-224"},"PeriodicalIF":12.2,"publicationDate":"2026-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146150817","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Longitudinal Profiling of Tumor and Immune Compartments Uncovers Patterns of Dysregulation and Associations with Response in Multiple Myeloma.","authors":"Denis J Ohlstrom, William C Pilcher, Marina E Michaud, Chaitanya Acharya, Sarthak Satpathy, Edgar Gonzalez-Kozlova, Reyka G Jayasinghe, Katherine Ferguson, Hope L Mumme, Shivani Nanda, Yizhe Song, Sowmitri Mantrala, Dimitra Karagkouni, Jessica Schulman, Nick Pabustan, Junia Vieira Dos Santos, Daniel W Sherbenou, Jonathan J Keats, Alexander M Gout, Steven Foltz, Alessandro Lagana, Taxiarchis Kourelis, Ravi Vij, Madhav V Dhodapkar, David Avigan, Hearn Jay Cho, Linda B Baughn, Ajay K Nooka, Sagar Lonial, Shaji Kumar, Mehmet K Samur, Ioannis S Vlachos, Li Ding, Sacha Gnjatic, George Mulligan, Manoj K Bhasin","doi":"10.1158/2643-3230.BCD-25-0205","DOIUrl":"10.1158/2643-3230.BCD-25-0205","url":null,"abstract":"<p><p>Multiple myeloma is a malignancy of clonally expanded plasma cells shaped by complex interactions with the immune microenvironment (IME). To investigate immune correlates of treatment response and disease progression, we conducted multi-omics profiling including CD138neg single-cell RNA sequencing of 243 bone marrow samples from 102 patients (631,226 cells) and CD138pos bulk RNA and whole-genome sequencing from 209 samples. In longitudinal analyses, interferon-γ signaling associated with markers of impaired T-cell memory after autologous stem cell transplant, whereas naïve B-cell abundance and immunoglobulin diversity correlated with improved progression-free survival (HR = 0.48; P = 2.3e-4). At disease progression, multiple myeloma cells upregulated cancer-testis antigens (CTAg) and immune effector genes, with concurrent B-cell depletion, enrichment of myeloid-derived suppressor cell expression, and phenotypic T-cell exhaustion. These findings highlight dynamic immune-tumor interactions, identifying naïve B-cell reconstitution as a biomarker of durable response and CTAgs as potential targets for high-risk disease at progression.</p><p><strong>Significance: </strong>Longitudinal profiling of multiple myeloma and the IME revealed dynamic immune-tumor interactions across the disease course. Altered expression in CD8+ T cells limited memory phenotype after transplant, whereas naïve B-cell recovery associated with sustained treatment response. At progression, CTAg expression associated with immunosuppression, revealing novel mechanisms of immune dysregulation.</p>","PeriodicalId":29944,"journal":{"name":"Blood Cancer Discovery","volume":" ","pages":"266-286"},"PeriodicalIF":12.2,"publicationDate":"2026-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13012255/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145716048","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":"A Pharmacologic Model Predicts that Tumor Debulking Improves CAR T-cell Efficacy in Large B-cell Lymphoma.","authors":"Amy E Pomeroy, Brian J Sworder, Deborah Plana, Yanguang Cao, Ash A Alizadeh, Adam C Palmer","doi":"10.1158/2643-3230.BCD-25-0138","DOIUrl":"10.1158/2643-3230.BCD-25-0138","url":null,"abstract":"<p><p>Chimeric antigen receptor (CAR) T cells produce durable remissions in some patients with large B-cell lymphoma, but outcomes are poor in patients with large tumor burdens or limited CAR T-cell expansion. To understand these relationships and explore potential interventions, we applied established population pharmacokinetic/pharmacodynamic principles to model kinetics of axicabtagene ciloleucel (axi-cel) concentrations and tumor responses to axi-cel, and validated model outputs using independent cohorts. This mechanistic model reproduces and explains poor outcomes associated with high tumor burden and low CAR T-cell expansion, finding that proliferation of large lymphoma populations can outpace the cytotoxic effect of CAR T cells. A high ratio of lymphoma cells to CAR T cells is effectively a mechanism of CAR T-cell resistance, which could be modified by tumor debulking before infusion. This model predicts that reducing tumor burden before CAR T-cell infusion may improve durable remission rate. Future clinical studies optimizing bridging therapy may therefore enhance the success of CAR T-cell therapies.</p><p><strong>Significance: </strong>A population pharmacokinetic/pharmacodynamic model of axi-cel in large B-cell lymphoma explains the observation that high tumor burden and low CAR T-cell expansion predict poor outcomes. This model suggests tumor debulking before CAR T infusion or deploying CAR T therapy in measurable residual disease-positive patients after first-line treatment could improve CAR T success rates. See related commentary by Altrock, p. 11.</p>","PeriodicalId":29944,"journal":{"name":"Blood Cancer Discovery","volume":" ","pages":"41-50"},"PeriodicalIF":12.2,"publicationDate":"2026-01-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12626407/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145379095","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":"(Sub)Clonal Wars: Interferon Interference Yields the Upper Hand.","authors":"Dimitrios Papaioannou, Iannis Aifantis","doi":"10.1158/2643-3230.BCD-25-0388","DOIUrl":"10.1158/2643-3230.BCD-25-0388","url":null,"abstract":"<p><p>Intratumoral heterogeneity and subclonal diversity, characterized by the coexistence of genetically and functionally distinct leukemic cell populations within a single patient, have long been recognized as major contributors to chemotherapy resistance and disease relapse in acute myeloid leukemia. In this issue of Blood Cancer Discovery, Karigane and colleagues delve into the mechanisms that underlie the interactions between distinct leukemic subpopulations and identify Interferon signaling as a critical regulator that determines clonal dominance and expansion. See related article by Karigane et al., p. 68.</p>","PeriodicalId":29944,"journal":{"name":"Blood Cancer Discovery","volume":" ","pages":"18-20"},"PeriodicalIF":12.2,"publicationDate":"2026-01-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145744871","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Golcadomide: An Oral CELMoD Agent Targeting IKZF1/3 for Diffuse Large B-cell Lymphoma.","authors":"Zhongying Mo, Lynda Groocock, Scott Wood, Diana Jankeel, Derek Mendy, Edmond R Watson, Yan Kai, Gauri Deb, Marjorie Cote, Preethi Janardhanan, Álvaro Fernández-Deudero, Leo Barnes, Sophie Peng, Matthew Groza, Evgenia Kalashnikova, Michael Angelo, Jinyi Zhu, Ryan Galasso, In Sock Jang, Manuel Sanchez Castillo, Celia Fontanillo, Geraldine Polido, Andy Christoforou, Timothy Kercher, Gabriel C Lander, Kai Wang, Rama Krishna Narla, Soraya Carrancio, Daniel W Pierce, Mark Rolfe, Neil Bence, Antonia Lopez-Girona","doi":"10.1158/2643-3230.BCD-25-0059","DOIUrl":"10.1158/2643-3230.BCD-25-0059","url":null,"abstract":"<p><p>Diffuse large B-cell lymphoma (DLBCL) is an aggressive and heterogeneous disease with limited treatment options and a poor prognosis, especially for patients refractory to standard therapies. We report the discovery of golcadomide (CC-99282), an oral cereblon-modulating CELMoD agent designed using target-specific knowledge and optimized pharmacologic properties for the treatment of DLBCL. Golcadomide exhibited rapid, deep, and sustained degradation of transcription factors IKZF1 and IKZF3, surpassing the antitumor activity of the IMiD agent lenalidomide in preclinical models. In human lymphoma cell lines, golcadomide downregulated MYC, activated IFN-stimulated genes, and promoted antiproliferation, apoptosis, and immunogenic cell death. In mouse xenografts, golcadomide preferentially distributed to tissues known to be affected by lymphoma, resulting in enhanced tumor regression and tumor-free outcomes. Pharmacologic and CRISPR screening further revealed genes and pathways underlying golcadomide's antitumor efficacy. These findings supported golcadomide as a promising drug candidate for DLBCL, providing a strong rationale for future golcadomide-based regimens.</p><p><strong>Significance: </strong>Golcadomide is an oral cereblon-modulating agent for the treatment of DLBCL. It exhibited rapid, deep, and sustained degradation of IKZF1 and IKZF3, preferentially accumulated in lymphoma residence tissues, and delivered robust antitumor activity. These results provide a strong rationale for continued clinical investigation of golcadomide for patients with DLBCL.</p>","PeriodicalId":29944,"journal":{"name":"Blood Cancer Discovery","volume":" ","pages":"104-128"},"PeriodicalIF":12.2,"publicationDate":"2026-01-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145439094","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"ID2 Suppresses Multiple Myeloma Cell Proliferation by Repressing the Activity of the Transcription Factor TCF3.","authors":"Mariateresa Fulciniti, Yao Yao, Tommaso Perini, Jessica Fong Ng, Anaïs Schavgoulidze, Shuhui Deng, Jian Cui, Jessica Encinas Mayoral, Francesco Ladisa, Ryan M Young, Charles B Epstein, Cassandra M White, Christopher J Ott, Annamaria Gulla, Shannon M Matulis, Adam S Sperling, Eugenio Morelli, Lawrence H Boise, Moritz Binder, Raphael Szalat, Mehmet K Samur, Kenneth C Anderson, Nikhil C Munshi","doi":"10.1158/2643-3230.BCD-25-0048","DOIUrl":"10.1158/2643-3230.BCD-25-0048","url":null,"abstract":"<p><p>Transcription factors and their cofactors are major and selective nononcogene dependencies in multiple myeloma cells. By performing a gain-of-function perturbation screen in human multiple myeloma cell lines, we identified the inhibitor of DNA binding (ID) genes as putative suppressors of multiple myeloma cell fitness. Among them, ID2 was found to be downregulated in multiple myeloma patient cells and acted as a tumor suppressor by directly binding and repressing the basic helix-loop-helix factor TCF3, also known as E2A. Lower ID2 expression in multiple myeloma cells conferred a proliferative advantage by increasing TCF3 activity, leading to a dependency on this transcription factor. In contrast, ID2 overexpression reduced TCF3 binding to DNA, which resulted in cell-cycle arrest and a halt in multiple myeloma cell proliferation. The myeloma bone marrow milieu supported this process by further decreasing the expression of ID2 and enhancing TCF3 activity, partly via IL6, revealing a mechanism by which the tumor microenvironment affects multiple myeloma cell behavior.</p><p><strong>Significance: </strong>Multiple myeloma cells exploit the oncogenic and proliferative potential of TCF3 by downregulating the transcriptional regulator ID2, a process facilitated by the bone marrow microenvironment.</p>","PeriodicalId":29944,"journal":{"name":"Blood Cancer Discovery","volume":" ","pages":"129-141"},"PeriodicalIF":12.2,"publicationDate":"2026-01-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12616536/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145309381","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":"Beyond Expansion: Tumor Debulking as Key to Improving CAR T-Cell Potential in Lymphoma.","authors":"Philipp M Altrock","doi":"10.1158/2643-3230.BCD-25-0397","DOIUrl":"10.1158/2643-3230.BCD-25-0397","url":null,"abstract":"<p><p>In this issue of Blood Cancer Discovery, Pomeroy and colleagues explore a population pharmacokinetic/pharmacodynamic model of axicabtagene ciloleucel in large B-cell lymphoma, quantifying how tumor debulking before chimeric antigen receptor (CAR) T-cell infusion can significantly improve durable remission rates. Their framework incorporates mechanistic modeling principles of CAR T-cell biology and therapy, such as CAR T-cell expansion, binding, killing, and stochastic CD19 loss, providing actionable insights for optimizing combination approaches and future trial design. See related article by Pomeroy et al., p. 41.</p>","PeriodicalId":29944,"journal":{"name":"Blood Cancer Discovery","volume":" ","pages":"11-14"},"PeriodicalIF":12.2,"publicationDate":"2026-01-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145565393","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Q&A with Ross Levine: From Biological Insights to Better Treatments for Myeloid Neoplasms.","authors":"","doi":"10.1158/2643-3230.BCD-25-0481","DOIUrl":"https://doi.org/10.1158/2643-3230.BCD-25-0481","url":null,"abstract":"","PeriodicalId":29944,"journal":{"name":"Blood Cancer Discovery","volume":"7 1","pages":"7-10"},"PeriodicalIF":11.5,"publicationDate":"2026-01-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145953246","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"PKCβ Inhibitor MS-553 Displays Preclinical Efficacy in Both Treatment-Naïve and BTK Inhibitor-Resistant Chronic Lymphocytic Leukemia.","authors":"Britten K Gordon, Elizabeth M Muhowski, Jyotsana Singh, Janani Ravikrishnan, Arnau Peris-Cuesta, Daisy Diaz Rohena, John R Sanchez, Shanmugapriya Thangavadivel, Samon Benrashid, Alexander He, Alexander R Marr, Andrew D Mitchell, Jazmin M Urrutia, Shrilekha Misra, Tzung-Huei Lai, Lianbo Yu, Brandi R Walker, Elizabeth Perry, Sachet A Shukla, Nicole R Grieselhuber, Kerry A Rogers, Rosa Lapalombella, James S Blachly, Adam S Kittai, Seema A Bhat, Nitin Jain, William G Wierda, John C Byrd, Michael Niesman, Kai Zhang, Deepa Sampath, Jennifer A Woyach","doi":"10.1158/2643-3230.BCD-25-0114","DOIUrl":"10.1158/2643-3230.BCD-25-0114","url":null,"abstract":"<p><p>Inhibition of the tyrosine kinase BTK is a major therapeutic strategy for treating B-cell malignancies, including chronic lymphocytic leukemia (CLL). However, resistance can emerge when tumor cells acquire mutations that abrogate drug binding or when BTK activates B-cell receptor (BCR) signaling by mechanisms independent of its kinase activity. In this study, we identified upregulation of PKCβ in samples from patients with CLL resistant to BTK inhibitors (BTKi) and characterized the PKCβ inhibitor MS-553. MS-553 reduced BCR and Wnt/β-catenin signaling, overcame stromal cell mediated protection, and synergized with venetoclax in CLL samples. MS-553 also retained the cytotoxicity and inhibition of both BCR and Wnt/β-catenin signaling in models (cell lines and primary samples) of covalent BTKi-resistant (C481S BTK) and noncovalent BTKi-resistant (T474I or L528W BTK) CLL. Furthermore, MS-553 delayed disease progression and prolonged survival in the Eμ-MTCP1 murine model of CLL. Collectively our results demonstrate that selective inhibition of PKCβ has the potential to overcome BTKi-resistant CLL.</p><p><strong>Significance: </strong>This study identified and characterized PKCβ as a therapeutic target in CLL, including CLL resistant to BTKis. Inhibition of PKCβ suppressed both BCR and Wnt/β-catenin signaling, delayed disease progression in vivo, overcame BTKi resistance mechanisms, and enhanced response to BCL-2 inhibition. See related commentary by Jebaraj and Stilgenbauer, p. 21.</p>","PeriodicalId":29944,"journal":{"name":"Blood Cancer Discovery","volume":" ","pages":"85-103"},"PeriodicalIF":12.2,"publicationDate":"2026-01-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145446102","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}