Leukemia最新文献

{"title":"The VLA-4 integrin is constitutively active in circulating chronic lymphocytic leukemia cells via BCR autonomous signaling: a novel anchor-independent mechanism exploiting soluble blood-borne ligands","authors":"Erika Tissino, Annalisa Gaglio, Antonella Nicolò, Federico Pozzo, Tamara Bittolo, Francesca Maria Rossi, Riccardo Bomben, Paola Nanni, Ilaria Cattarossi, Eva Zaina, Anna Maria Zimbo, Giulia Ianna, Guido Capasso, Gabriela Forestieri, Riccardo Moia, Moumita Datta, Andrea Härzschel, Jacopo Olivieri, Giovanni D’Arena, Luca Laurenti, Francesco Zaja, Annalisa Chiarenza, Giuseppe A. Palumbo, Enrica Antonia Martino, Massimo Gentile, Davide Rossi, Gianluca Gaidano, Giovanni Del Poeta, Roberta Laureana, Maria Ilaria Del Principe, Palash C. Maity, Hassan Jumaa, Tanja Nicole Hartmann, Antonella Zucchetto, Valter Gattei","doi":"10.1038/s41375-024-02376-7","DOIUrl":"10.1038/s41375-024-02376-7","url":null,"abstract":"In chronic lymphocytic leukemia (CLL), survival of neoplastic cells depends on microenvironmental signals at lymphoid sites where the crosstalk between the integrin VLA-4 (CD49d/CD29), expressed in ~40% of CLL, and the B-cell receptor (BCR) occurs. Here, BCR engagement inside–out activates VLA-4, thus enhancing VLA-4-mediated adhesion of CLL cells, which in turn obtain pro-survival signals from the surrounding microenvironment. We report that the BCR is also able to effectively inside–out activate the VLA-4 integrin in circulating CD49d-expressing CLL cells through an autonomous antigen-independent BCR signaling. As a consequence, circulating CLL cells exhibiting activated VLA-4 express markers of BCR pathway activation (phospho-BTK and phospho-PLC-γ2) along with higher levels of phospho-ERK and phospho-AKT indicating parallel activation of downstream pathways. Moreover, circulating CLL cells expressing activated VLA-4 bind soluble blood-borne VCAM-1 leading to increased VLA-4-dependent actin polymerization/re-organization and ERK phosphorylation. Finally, evidence is provided that ibrutinib treatment, by affecting autonomous BCR signaling, impairs the constitutive VLA-4 activation eventually decreasing soluble VCAM-1 binding and reducing downstream ERK phosphorylation by circulating CLL cells. This study describes a novel anchor-independent mechanism occurring in circulating CLL cells involving the BCR and the VLA-4 integrin, which help to unravel the peculiar biological and clinical features of CD49d+ CLL.","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":null,"pages":null},"PeriodicalIF":12.8,"publicationDate":"2024-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41375-024-02376-7.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141980816","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":"Loss of Dnajc21 leads to cytopenia and altered nucleotide metabolism in zebrafish","authors":"Sarada Ketharnathan, Sujata Pokharel, Sergey V. Prykhozhij, Anna Cordeiro-Santanach, Kevin Ban, Serkan Dogan, Huy-Dung Hoang, Mira F. Liebman, Elaine Leung, Tommy Alain, Irina Alecu, Steffany A. L. Bennett, Miroslava Čuperlović-Culf, Yigal Dror, Jason N. Berman","doi":"10.1038/s41375-024-02367-8","DOIUrl":"10.1038/s41375-024-02367-8","url":null,"abstract":"Mutations in the DNAJC21 gene were recently described in Shwachman–Diamond syndrome (SDS), a bone marrow failure syndrome with high predisposition for myeloid malignancies. To study the underlying biology in hematopoiesis regulation and disease, we generated the first in vivo model of Dnajc21 deficiency using the zebrafish. Zebrafish dnajc21 mutants phenocopy key SDS patient phenotypes such as cytopenia, reduced growth, and defective protein synthesis. We show that cytopenia results from impaired hematopoietic differentiation, accumulation of DNA damage, and reduced cell proliferation. The introduction of a biallelic tp53 mutation in the dnajc21 mutants leads to the development of myelodysplastic neoplasia-like features defined by abnormal erythroid morphology and expansion of hematopoietic progenitors. Using transcriptomic and metabolomic analyses, we uncover a novel role for Dnajc21 in nucleotide metabolism. Exogenous nucleoside supplementation restores neutrophil counts, revealing an association between nucleotide imbalance and neutrophil differentiation, suggesting a novel mechanism in dnajc21-mutant SDS biology.","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":null,"pages":null},"PeriodicalIF":12.8,"publicationDate":"2024-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41375-024-02367-8.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141973875","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":"GNAS knockout potentiates HDAC3 inhibition through viral mimicry-related interferon responses in lymphoma","authors":"Michael Y. He, Kit I. Tong, Ting Liu, Ryder Whittaker Hawkins, Victoria Shelton, Yong Zeng, Mehran Bakhtiari, Yufeng Xiao, Guangrong Zheng, Ali Sakhdari, Lin Yang, Wenxi Xu, David G. Brooks, Rob C. Laister, Housheng Hansen He, Robert Kridel","doi":"10.1038/s41375-024-02325-4","DOIUrl":"10.1038/s41375-024-02325-4","url":null,"abstract":"Despite selective HDAC3 inhibition showing promise in a subset of lymphomas with CREBBP mutations, wild-type tumors generally exhibit resistance. Here, using unbiased genome-wide CRISPR screening, we identify GNAS knockout (KO) as a sensitizer of resistant lymphoma cells to HDAC3 inhibition. Mechanistically, GNAS KO-induced sensitization is independent of the canonical G-protein activities but unexpectedly mediated by viral mimicry-related interferon (IFN) responses, characterized by TBK1 and IRF3 activation, double-stranded RNA formation, and transposable element (TE) expression. GNAS KO additionally synergizes with HDAC3 inhibition to enhance CD8+ T cell-induced cytotoxicity. Moreover, we observe in human lymphoma patients that low GNAS expression is associated with high baseline TE expression and upregulated IFN signaling and shares common disrupted biological activities with GNAS KO in histone modification, mRNA processing, and transcriptional regulation. Collectively, our findings establish an unprecedented link between HDAC3 inhibition and viral mimicry in lymphoma. We suggest low GNAS expression as a potential biomarker that reflects viral mimicry priming for enhanced response to HDAC3 inhibition in the clinical treatment of lymphoma, especially the CREBBP wild-type cases.","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":null,"pages":null},"PeriodicalIF":12.8,"publicationDate":"2024-08-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41375-024-02325-4.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141904298","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":"Transfusion independence after lenalidomide discontinuation in patients with del(5q) myelodysplastic neoplasm: a HARMONY Alliance study","authors":"Elena Crisà, Elvira Mora, Ulrich Germing, Cecile Bally, Maria Diez Campelo, Mikko Myllymäki, Martin Jädersten, Rami Komrokji, Uwe Platzbecker, Detlef Haase, Wolf-Karsten Hofmann, Najla H. Al Ali, Daniela Barraco, Juan José Bargay, Teresa Bernal, Felix López Cadenas, Anna Calvisi, Isabella Capodanno, Marco Cerrano, Rosanna Ciancia, Monica Crugnola, Andrea Kündgen, Carlo Finelli, Claudio Fozza, Chiara Frairia, Ebeling Freja, Christina Ganster, Anne Sophie Kubasch, Maria Jose Jimenez, Roberto Latagliata, Francisca Hernandez Mohedo, Antonieta Molero, Miriam Vara Pampliega, Clara Aparicio Perez, Giuseppe Pietrantuono, Antonella Poloni, Helena Pomares, Valle Recasens, Axel Rüfer, Alessio Signori, Eva Hellstrom-Lindberg, Pierre Fenaux, Guillermo Sanz, Valeria Santini","doi":"10.1038/s41375-024-02360-1","DOIUrl":"10.1038/s41375-024-02360-1","url":null,"abstract":"Lenalidomide (LEN) can induce red blood cell-transfusion independence (RBC-TI) in 60–70% of del(5q) myelodysplastic neoplasm (MDS) patients. Current recommendation is to continue LEN in responding patients until failure or progression, with likelihood of toxicity and a high cost for healthcare systems. This HARMONY Alliance study investigated the outcome of MDS del(5q) patients who discontinued LEN while RBC-transfusion independent. We enrolled 118 patients with IPSS-R low-intermediate risk. Seventy patients (59%) discontinued LEN for intolerance, 38 (32%) per their physician decision, nine (8%) per their own decision and one (1%) for unknown reasons. After a median follow-up of 49 months from discontinuation, 50/118 patients lost RBC-TI and 22/30 who underwent cytogenetic re-evaluation lost complete cytogenetic response. The median RBC-TI duration was 56 months. In multivariate analysis, RBC-TI duration after LEN discontinuation correlated with low transfusion burden before LEN therapy, treatment ≥ 12 LEN cycles, younger age and higher Hb level at LEN withdrawal. Forty-eight patients were re-treated with LEN for loss of response and 28 achieved again RBC-TI. These data show that stopping LEN therapy in MDS del(5q) patients who reached RBC-TI allows prolonged maintenance of TI in a large subset of patients.","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":null,"pages":null},"PeriodicalIF":12.8,"publicationDate":"2024-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141893777","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"BCR::ABL1 Proteolysis-targeting chimeras (PROTACs): The new frontier in the treatment of Ph+ leukemias?","authors":"Nataly Cruz-Rodriguez, Hua Tang, Benjamin Bateman, Weiping Tang, Michael Deininger","doi":"10.1038/s41375-024-02365-w","DOIUrl":"10.1038/s41375-024-02365-w","url":null,"abstract":"BCR::ABL1 tyrosine kinase inhibitors (TKIs) have turned chronic myeloid leukemia (CML) from a lethal condition into a chronic ailment. With optimal management, the survival of CML patients diagnosed in the chronic phase is approaching that of age-matched controls. However, only one-third of patients can discontinue TKIs and enter a state of functional cure termed treatment-free remission (TFR), while the remainder require life-long TKI therapy to avoid the recurrence of active leukemia. Approximately 10% of patients exhibit primary or acquired TKI resistance and eventually progress to the blast phase. It is thought that recurrence after attempted TFR originates from CML stem cells (LSCs) surviving despite continued suppression of BCR::ABL1 kinase. Although kinase activity is indispensable for induction of overt CML, kinase-independent scaffold functions of BCR::ABL1 are known to contribute to leukemogenesis, raising the intriguing but as yet hypothetical possibility, that degradation of BCR::ABL1 protein may accomplish what TKIs fail to achieve – eliminate residual LSCs to turn functional into real cures. The advent of BCR::ABL1 proteolysis targeting chimeras (PROTACs), heterobifunctional molecules linking a TKI-based warhead to an E3 ligase recruiter, has moved clinical protein degradation into the realm of the possible. Here we examine the molecular rationale as well as pros and cons of degrading BCR::ABL1 protein. We review reported BCR::ABL1 PROTACs, point out limitations of available data and compounds and suggest directions for future research. Ultimately, clinical testing of a potent and specific BCR::ABL1 degrader will be required to determine the efficacy and tolerability of this approach.","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":null,"pages":null},"PeriodicalIF":12.8,"publicationDate":"2024-08-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41375-024-02365-w.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141887417","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":"Rational combinatorial targeting by adapter CAR-T-cells (AdCAR-T) prevents antigen escape in acute myeloid leukemia","authors":"Daniel Atar, Lara Ruoff, Anna-Sophia Mast, Simon Krost, Moustafa Moustafa-Oglou, Sophia Scheuermann, Beate Kristmann, Maximilian Feige, Aysegül Canak, Kathrin Wolsing, Lennart Schlager, Karin Schilbach, Latifa Zekri, Martin Ebinger, Daniel Nixdorf, Marion Subklewe, Johannes Schulte, Claudia Lengerke, Irmela Jeremias, Niels Werchau, Joerg Mittelstaet, Peter Lang, Rupert Handgretinger, Patrick Schlegel, Christian M. Seitz","doi":"10.1038/s41375-024-02351-2","DOIUrl":"10.1038/s41375-024-02351-2","url":null,"abstract":"Targeting AML by chimeric antigen receptor T-cells (CAR-T) is challenging due to the promiscuous expression of AML-associated antigens in healthy hematopoiesis and high degree of inter- and intratumoral heterogeneity. Here, we present single-cell expression data of AML-associated antigens in 30 primary pediatric AML samples. We identified CD33, CD38, CD371, IL1RAP and CD123 as the most frequently expressed. Notably, high variability was observed not only across the different patient samples but also among leukemic cells of the same patient suggesting the necessity of multiplexed targeting approaches. To address this need, we utilized our modular Adapter CAR (AdCAR) platform, enabling precise qualitative and quantitative control over CAR-T-cell function. We show highly efficient and target-specific activity for newly generated adapter molecules (AMs) against CD33, CD38, CD123, CD135 and CD371, both in vitro and in vivo. We reveal that inherent intratumoral heterogeneity in antigen expression translates into antigen escape and therapy failure to monotargeted CAR-T therapy. Further, we demonstrate in PDX models that rational combinatorial targeting by AdCAR-T-cells can cure heterogenic disease. In conclusion, we elucidate the clinical relevance of heterogeneity in antigen expression in pediatric AML and present a novel concept for precision immunotherapy by combinatorial targeting utilizing the AdCAR platform.","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":null,"pages":null},"PeriodicalIF":12.8,"publicationDate":"2024-08-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41375-024-02351-2.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141878965","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":"Clinical implications of residual normal plasma cells within bone marrow across various disease stages in multiple myeloma","authors":"Wenqiang Yan, Lihui Shi, Jingyu Xu, Lingna Li, Jian Cui, Yuntong Liu, Jieqiong Zhou, Chenxing Du, Tengteng Yu, Shuaishuai Zhang, Rui Lv, Weiwei Sui, Shuhui Deng, Xiaoqing Li, Xin Du, Yan Xu, Dehui Zou, Lugui Qiu, Mu Hao, Gang An","doi":"10.1038/s41375-024-02366-9","DOIUrl":"10.1038/s41375-024-02366-9","url":null,"abstract":"Residual normal plasma cells (NPCs), which compete with tumor plasma cells, play an important role in multiple myeloma. However, large-scale cohort studies investigating residual NPCs, especially at the minimal residual disease (MRD) phase, are currently lacking. In this study, we conducted a comprehensive investigation into the clinical significance of residual NPCs throughout the entire disease course in 1363 myeloma patients from the NICHE cohort (NCT04645199). Our results revealed that myeloma patients with high baseline NPCs ratio (≥5%) exhibited distinct indolent features, characterized by lower tumor burden, reduced frequencies of cytopenia, immunoparesis, and high-risk cytogenetics. Importantly, high residual NPCs ratio at diagnosis or relapse was independently associated with favorable survival. High absolute percentages of NPCs at undetectable MRD were related with superior clinical benefit and immune reconstitution. At MRD-positive phases, grouping based on NPCs ratio (<50%, 50–90%, ≥90%) demonstrated better risk stratification compared to residual tumor log levels. Based on the time-dependent NPCs ratio trend, we developed a dynamic MRD model that classifies patients into three groups with diverse longitudinal trends, leading to distinct prognoses. Collectively, residual NPCs serves not only as a valuable complementary biomarker for risk stratification but also provides valuable insights on reclassifications and kinetics of MRD.","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":null,"pages":null},"PeriodicalIF":12.8,"publicationDate":"2024-08-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41375-024-02366-9.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141878964","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":"Absence of ABL1 exon 2-encoded SH3 residues in BCR::ABL1 destabilizes the autoinhibited kinase conformation and confers resistance to asciminib","authors":"Ariel Leyte-Vidal, RosaAnna DeFilippis, Ian R. Outhwaite, Isabelle Kwan, Ji Young Lee, Carlyn Leavitt, Kaeli B. Miller, Delphine Rea, Aziz M. Rangwala, Kevin Lou, Suhana Patel, Ailin Alvarez, Kevan M. Shokat, Ivet Bahar, Markus A. Seeliger, Neil P. Shah","doi":"10.1038/s41375-024-02353-0","DOIUrl":"10.1038/s41375-024-02353-0","url":null,"abstract":"","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":null,"pages":null},"PeriodicalIF":12.8,"publicationDate":"2024-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41375-024-02353-0.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141857797","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":"Tumor evolution analysis uncovered immune-escape related mutations in relapse of diffuse large B-cell lymphoma","authors":"Xueshuai Han, Jingru Sui, Kui Nie, Yang Zhao, Xuan Lv, Jindou Xie, Leonard Tan, Rex K. H. Au-Yeung, Jiao Ma, Giorgio Inghirami, Olivier Elemento, Wayne Tam, Zhaoqi Liu","doi":"10.1038/s41375-024-02349-w","DOIUrl":"10.1038/s41375-024-02349-w","url":null,"abstract":"","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":null,"pages":null},"PeriodicalIF":12.8,"publicationDate":"2024-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141855912","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"REXO5 promotes genomic integrity through regulating R-loop using its exonuclease activity","authors":"Ye Jin Lee, Seo Yun Lee, Soomi Kim, Soo-Hyun Kim, Soo Hyeon Lee, Sungho Park, Jae Jin Kim, Dong-Wook Kim, Hongtae Kim","doi":"10.1038/s41375-024-02362-z","DOIUrl":"10.1038/s41375-024-02362-z","url":null,"abstract":"Chronic myeloid leukemia (CML), caused by BCR::ABL1 fusion gene, is known to regulate disease progression by altering the expression of genes. However, the molecular mechanisms underlying these changes are largely unknown. In this study, we identified RNA Exonuclease 5 (REXO5/LOC81691) as a novel gene with elevated mRNA expression levels in chronic myeloid leukemia (CML) patients. Additionally, using the REXO5 knockout (KO) K562 cell lines, we revealed a novel role for REXO5 in the DNA damage response (DDR). Compared to wild-type (WT) cells, REXO5 KO cells showed an accumulation of R-loops and increased DNA damage. We demonstrated that REXO5 translocates to sites of DNA damage through its RNA recognition motif (RRM) and selectively binds to R loops. Interestingly, we identified that REXO5 regulates R-loop levels by degrading mRNA within R-loop using its exonuclease domain. REXO5 KO showed ATR-CHK1 activation. Collectively, we demonstrated that REXO5 plays a key role in the physiological control of R-loops using its exonuclease domain. These findings may provide novel insights into how REXO5 expression changes contribute to CML pathogenesis.","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":null,"pages":null},"PeriodicalIF":12.8,"publicationDate":"2024-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41375-024-02362-z.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141855911","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}