Gioia Di Stefano, Anja Fischer, Emil Chteinberg, Susanne Bens, Rabea Wagener, Dmitriy Abramov, Patrick Adam, Stephan H. Bernhart, Arndt Borkhardt, Birgit Burkhardt, Coral Del-Val, Michael C. Frühwald, Raffaella Guazzo, Jessica I. Hoell, Michael Hummel, Heike Horn, Wolfram Klapper, Jens Krugmann, Katrin S. Kurz, Stefano Lazzi, Abner Jr. Louissaint, Anja Mottok, Ilske Oschlies, Raffaella Santi, Kristian Schafernak, Annette M. Staiger, Yanming Zhang, Andreas Rosenwald, Lorenz Trümper, Lorenzo Leoncini, German Ott, Reiner Siebert
{"title":"MicroRNA Expression in High-Grade B-Cell Lymphoma With 11q Aberration","authors":"Gioia Di Stefano, Anja Fischer, Emil Chteinberg, Susanne Bens, Rabea Wagener, Dmitriy Abramov, Patrick Adam, Stephan H. Bernhart, Arndt Borkhardt, Birgit Burkhardt, Coral Del-Val, Michael C. Frühwald, Raffaella Guazzo, Jessica I. Hoell, Michael Hummel, Heike Horn, Wolfram Klapper, Jens Krugmann, Katrin S. Kurz, Stefano Lazzi, Abner Jr. Louissaint, Anja Mottok, Ilske Oschlies, Raffaella Santi, Kristian Schafernak, Annette M. Staiger, Yanming Zhang, Andreas Rosenwald, Lorenz Trümper, Lorenzo Leoncini, German Ott, Reiner Siebert","doi":"10.1002/gcc.70021","DOIUrl":"10.1002/gcc.70021","url":null,"abstract":"<p>Mature aggressive B-cell lymphomas, such as Burkitt lymphoma (BL) and Diffuse large B-cell lymphoma (DLBCL), show variations in microRNA (miRNA) expression. The entity of High-grade B-cell lymphoma with 11q aberration (HGBCL-11q) shares several biological features with both BL and DLBCL but data on its miRNA expression profile are yet scarce. Hence, this study aims to analyze the potential differences in miRNA expression of HGBCL-11q compared to BL and DLBCL. We evaluated the expression profiles of 2083 miRNAs in 25 HGCBL-11q, 7 BL, 131 DLBCL, and tonsils using the HTG EdgeSeq miRNA whole transcriptome assay. Uniform manifold approximation and projection (UMAP) and differential gene expression analyses based on DESeq2 were carried out. UMAP analysis of miRNA expression did not reveal distinct groups among the studied lymphomas. However, differential gene expression investigations detected sets of overexpressed miRNAs in HGBCL-11q when compared to BL (miR-9-3p, miR-9-5p, miR-3919, miR-129-1-3p, miR-129-2-3p, miR-331-3p, miR-196b-5p, and miR-28-5p) and DLBCL (miR-3919, miR-1290, miR-4538, and miR-4791), respectively. Notably, miR-3919 showed heterogeneous but significantly higher expression (<i>p</i>-value < 0.001) in HGBCL-11q than in both, BL and DLBCL. We identified a group of differentially expressed miRNAs between HGBCL-11q vs. BL and DLBCL, with miR-3919 as the most commonly and recurrently overexpressed miRNA in HGBCL-11q.</p>","PeriodicalId":12700,"journal":{"name":"Genes, Chromosomes & Cancer","volume":"64 1","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11755218/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143023176","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":"A Bibliometric Analysis on the Risk Factors of Cancer","authors":"Shan Chen, Yuanzhao Ding","doi":"10.1002/gcc.70019","DOIUrl":"10.1002/gcc.70019","url":null,"abstract":"<div>\u0000 \u0000 <p>Given the high lethality of cancer, identifying its risk factors is crucial in both epidemiology and cancer research. This study employs a novel bibliometric analysis method, which uses the tidytext package and tidy tools in R. This approach surpasses traditional tools like VOSviewer, offering more comprehensive and complex keyword data and clearer results compared to Bibliometrix. By using R, researchers can efficiently handle useful keywords, ignore irrelevant terms, adjust specific settings, and correct errors such as repeated evaluations. This study examines 1000 articles sourced from the Web of Science database, using advanced bibliometric tools like R Studio to analyze publication quantity, frequency, and word co-occurrences. The primary goal is to uncover key risk factors associated with cancer and explore the underlying mechanisms that link these factors to cancer development. Risk factors are categorized into exogenous (environmental exposures and lifestyle choices) and endogenous (genetic predispositions and hormonal imbalances). By providing a comprehensive analysis of these factors, the study aims to deepen our understanding of cancer risk. This research contributes valuable insights to the broader field of cancer research and has the potential to inform future studies and strategies for cancer prevention and treatment.</p>\u0000 </div>","PeriodicalId":12700,"journal":{"name":"Genes, Chromosomes & Cancer","volume":"64 1","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143004333","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Takeshi Hirose, Hsin-Yi Chang, Carla Saoud, Robert A. Lefkowitz, Edward Athanasian, Cristina R. Antonescu
{"title":"A Clinicopathologic and Molecular Reappraisal of Myxoinflammatory Fibroblastic Sarcoma—A Controversial and Pathologically Challenging Low-Grade Sarcoma","authors":"Takeshi Hirose, Hsin-Yi Chang, Carla Saoud, Robert A. Lefkowitz, Edward Athanasian, Cristina R. Antonescu","doi":"10.1002/gcc.70018","DOIUrl":"10.1002/gcc.70018","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Purpose</h3>\u0000 \u0000 <p>Myxoinflammatory fibroblastic sarcoma (MIFS) is a rare, low-grade sarcoma affecting with predilection the acral soft tissues of middle-aged adults. Clinically, MIFS is associated with a high rate of local recurrence but infrequent distant metastases. The diagnosis remains challenging due to their wide histologic spectrum and overlap with reactive, benign, and low-grade malignant lesions. Moreover, a significant limitation is that molecular confirmation is achieved in only a subset of cases, due to its broad range of genetic alterations which requires a multiplatform approach. Thus, a definitive diagnosis, especially at nonacral sites and in molecularly negative cases, remains uncertain. Our goal was to perform a detailed clinicopathologic and molecular reappraisal of MIFS managed at a single tertiary cancer center with dedicated orthopedic oncology expertise. Additionally, we examined potential outcomes correlating with specific genetic alterations.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Patients and Methods</h3>\u0000 \u0000 <p>A cohort of 33 patients (12 males, 21 females, median age 52 years) was selected. Tumors were tested by FISH, Archer, and/or targeted NGS.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p><i>VGLL3</i> amplification was detected in 84%, <i>BRAF</i> fusions in 33% and combined <i>TGFBR3/MGEA5</i> rearrangements in 32% of cases. Two novel fusions were detected, <i>RRAGB::CCNB3</i> and <i>FGFR1::ZBTB47</i>. Other events included a <i>YAP1::MAML2</i> fusion in two cases, one co-existing with a <i>BRAF</i> fusion. Overall, 8 (24%) patients recurred, 4 more than once, while 4 (12%) patients developed metastasis (3 locoregional, 1 pulmonary), all associated with <i>VGLL3</i> gene amplification.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Positive margin status was associated with increased recurrence and reduced disease-free survival (DFS, <i>p</i> = 0.02). Moreover, it emphasizes the impact of multiplatform molecular testing in confirming the diagnosis. The lack of both local recurrence and metastatic potential outside <i>VGLL3</i> amplifications requires further investigation.</p>\u0000 </section>\u0000 </div>","PeriodicalId":12700,"journal":{"name":"Genes, Chromosomes & Cancer","volume":"64 1","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-01-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143004334","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"SMARCA4 Deficiency in Lung Cancer: From Signaling Pathway to Potential Therapeutic Targets","authors":"Mingzhu Zhang, Youhong Dong, Rui Meng, Dongdong Zhang","doi":"10.1002/gcc.70022","DOIUrl":"10.1002/gcc.70022","url":null,"abstract":"<div>\u0000 \u0000 <p>SMARCA4-deficient lung cancer, including thoracic SMARCA4-deficient undifferentiated tumors and SMARCA4-deficient nonsmall-cell lung carcinomas, is a rare and aggressive disease characterized by rapid progression and poor prognosis. This cancer was identified as a distinct entity with specific morphologic and molecular features in the 2021 WHO Classification of Thoracic Tumors. Molecular alterations in SMARCA4 are specific to this type of lung cancer. Deficiency in SMARCA4 suppresses the SWI/SNF tumor suppressor complex, driving tumor progression. Due to the lack of standardized treatment, most patients succumb to the disease within 6 months. This study provides a detailed analysis of the SMARCA4 pathway and its role in lung cancer. We analyzed potential therapeutic targets and agents to offer insights for the precise and effective treatment of SMARCA4-deficient lung cancer.</p>\u0000 </div>","PeriodicalId":12700,"journal":{"name":"Genes, Chromosomes & Cancer","volume":"64 1","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142983294","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Maryam Kakay Afshari, Paloma Tejera Nevado, André Fehr, Junchi Huang, Fredrik Jäwert, Jonas A. Nilsson, Göran Stenman, Mattias K. Andersson
{"title":"The Transcriptomic and Gene Fusion Landscape of Pleomorphic Salivary Gland Adenomas","authors":"Maryam Kakay Afshari, Paloma Tejera Nevado, André Fehr, Junchi Huang, Fredrik Jäwert, Jonas A. Nilsson, Göran Stenman, Mattias K. Andersson","doi":"10.1002/gcc.70023","DOIUrl":"10.1002/gcc.70023","url":null,"abstract":"<p>Pleomorphic adenoma (PA) is the most common salivary gland tumor. PAs are characterized by chromosomal rearrangements of 8q12 and 12q14-15, leading to gene fusions involving the <i>PLAG1</i> and <i>HMGA2</i> oncogenes. Here, we performed the first comprehensive study of the transcriptomic and gene fusion landscape of 38 cytogenetically characterized PAs. RNA-seq identified <i>PLAG1</i> or <i>HMGA2</i> fusions in 33/38 cases (87%), of which 15 were novel fusions. Fusions were found also in tumors with normal karyotype, demonstrating that they are generated by cryptic rearrangements. <i>PLAG1</i> was mainly activated by promoter swapping and <i>HMGA2</i> by truncation of its 3′-part. RNA-seq revealed upregulation of genes involved in extracellular matrix production, WNT-signaling, and epithelial-mesenchymal transition in PA compared to normal salivary tissue. Principal component analysis identified two PA subclusters characterized by <i>PLAG1</i>- and <i>HMGA2</i>-activation, respectively, that differed in expression of genes involved in the immune system, cell adhesion, and microenvironment remodeling. Moreover, comparative analyses of PA and salivary carcinomas revealed that PA resembles myoepithelial carcinoma. Our study reveals new oncogenic gene fusions and expands our knowledge about the molecular underpinnings of PA.</p>","PeriodicalId":12700,"journal":{"name":"Genes, Chromosomes & Cancer","volume":"64 1","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11734380/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142983295","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}
Fleur Cordier, Liesbeth Ferdinande, Siebe Loontiens, Joni Van der Meulen, Jo Van Dorpe, David Creytens
{"title":"A Challenging Case of an Intraosseous Composite Hemangioendothelioma of the Occipital Bone With YAP1::FOXR1 Fusion","authors":"Fleur Cordier, Liesbeth Ferdinande, Siebe Loontiens, Joni Van der Meulen, Jo Van Dorpe, David Creytens","doi":"10.1002/gcc.70016","DOIUrl":"10.1002/gcc.70016","url":null,"abstract":"","PeriodicalId":12700,"journal":{"name":"Genes, Chromosomes & Cancer","volume":"63 12","pages":""},"PeriodicalIF":3.1,"publicationDate":"2024-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142785051","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Anair Graciela Lema Fernandez, Carlotta Nardelli, Valentina Pierini, Barbara Crescenzi, Fabrizia Pellanera, Caterina Matteucci, Maria Crocioni, Silvia Arniani, Valeria Di Battista, Martina Quintini, Giada Mondanelli, Ciriana Orabona, Paolo Gorello, Cristina Mecucci
{"title":"Epigenetic Modeling of Jumping Translocations of 1q Heterochromatin in Acute Myeloid Leukemia After 5'-Azacytidine Treatment","authors":"Anair Graciela Lema Fernandez, Carlotta Nardelli, Valentina Pierini, Barbara Crescenzi, Fabrizia Pellanera, Caterina Matteucci, Maria Crocioni, Silvia Arniani, Valeria Di Battista, Martina Quintini, Giada Mondanelli, Ciriana Orabona, Paolo Gorello, Cristina Mecucci","doi":"10.1002/gcc.70013","DOIUrl":"10.1002/gcc.70013","url":null,"abstract":"<p>Jumping translocations (JT) are rare cytogenetic abnormalities associated with progression in myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). Typically, a tri–tetra-somic 1q chromosome is translocated to two or more recipient chromosomes. In multiple myeloma JT were shown to originate after DNA demethylation and decondensation. Using epigenomics, we investigated sequential samples in an <i>SRSF2</i>-mutated MDS and AML cohort with normal karyotype at diagnosis and 1qJT at disease evolution after 5′-azacytidine (AZA). 1qJT breakpoints fell within repetitive DNA at both 1q12 and the translocation partners, namely acrocentrics n. 14, 15, 21, and 22, chromosome 16, and chromosome Y. The global methylome at diagnosis showed hypermethylation at 61% of the differentially methylated regions (DMRs), followed by hypomethylation at 80% of DMRs under AZA, mostly affecting pathways related to immune system, chromatin organization, chromosome condensation, telomere maintenance, rRNA, and DNA repair. At disease evolution, a shift toward hypermethylation, intronic enhancers enrichment and epigenetic involvement of the PI3K/AKT and MAPK signaling emerged. In particular, AKT1 phosphorylation behaved as a hallmark of the progression. Overall, we provided new insights on the characterization of 1qJT in <i>SRSF2</i>-mutated myeloid neoplasms and first showed that epigenetics is a powerful tool to investigate the molecular landscape of repetitive DNA rearrangements.</p>","PeriodicalId":12700,"journal":{"name":"Genes, Chromosomes & Cancer","volume":"63 11","pages":""},"PeriodicalIF":3.1,"publicationDate":"2024-11-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/gcc.70013","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142739271","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}
Nooshin K. Dashti, George Matcuk, Abbas Agaimy, Carla Saoud, Cristina R. Antonescu
{"title":"Malignant Bone-Forming Neoplasm With NIPBL::BEND2 Fusion","authors":"Nooshin K. Dashti, George Matcuk, Abbas Agaimy, Carla Saoud, Cristina R. Antonescu","doi":"10.1002/gcc.70015","DOIUrl":"10.1002/gcc.70015","url":null,"abstract":"<div>\u0000 \u0000 <p>Conventional high-grade osteosarcomas are characterized by aggressive radiologic features, cytologic pleomorphism, and complex genomics. However, rare examples of osteosarcomas remain challenging due to unusual histology, such as sclerosing or osteoblastoma-like features, which may require molecular confirmation of their complex genetic alterations. We have encountered such a case in a 17-year-old man, who presented with a third metatarsal sclerotic bone lesion, found incidentally in the work-up of a foot trauma. The initial imaging revealed a lesion with sclerotic/blastic features proximally and lucent/lytic portion distally, findings interpreted consistent with osteoblastoma. The lesion was managed intra-lesionally with curettings and cryoablation; however, the microscopic findings were non-specific, showing a bland osteoblastic proliferation embedded in a densely sclerotic matrix. Subsequently, the patient developed two rapid recurrences; the first recurrence was treated similarly despite its associated soft tissue extension radiographically, and the histologic findings remained non-specific. The 2nd recurrence showed a large mass, with bone destruction and soft tissue extension and an open biopsy revealed features of osteosarcoma with lace-like osteoid deposition, albeit with uniform cytomorphology. The subsequent below knee amputation showed features compatible with high-grade osteosarcoma, including solid growth of uniform epithelioid cells, with vesicular nuclei and scant cytoplasm, set in a lace-like meshwork of osteoid matrix. There was significant mitotic activity and tumor necrosis. Tumor cells were positive for SATB2. Further molecular work-up was performed showing an unexpected <i>NIPBL::BEND2</i> fusion, which has been previously reported in two cases of phosphaturic mesenchymal tumor (PMT). FGF23 (ISH) was performed and was negative. By DNA methylation profiling, unsupervised clustering and UMAP dimensionality reduction revealed grouping with high-grade osteosarcomas and not with the PMT group. The patient received chemotherapy post-amputation and is alive without evidence of disease, with 10-month follow-up. We report an aggressive, overtly malignant acral bone-forming tumor, harboring a <i>NIPBL::BEND2</i> fusion. Further studies are needed to evaluate the recurrent potential of this fusion in osteosarcomas and its relationship with PMT.</p>\u0000 </div>","PeriodicalId":12700,"journal":{"name":"Genes, Chromosomes & Cancer","volume":"63 11","pages":""},"PeriodicalIF":3.1,"publicationDate":"2024-11-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142739273","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Shuhao Fan, Jianhua Guo, Hui Nie, Huabao Xiong, Yong Xia
{"title":"Aberrant Energy Metabolism in Tumors and Potential Therapeutic Targets","authors":"Shuhao Fan, Jianhua Guo, Hui Nie, Huabao Xiong, Yong Xia","doi":"10.1002/gcc.70008","DOIUrl":"https://doi.org/10.1002/gcc.70008","url":null,"abstract":"<p>Energy metabolic reprogramming is frequently observed during tumor progression as tumor cells necessitate adequate energy production for rapid proliferation. Although current medical research shows promising prospects in studying the characteristics of tumor energy metabolism and developing anti-tumor drugs targeting energy metabolism, there is a lack of systematic compendiums and comprehensive reviews in this field. The objective of this study is to conduct a systematic review on the characteristics of tumor cells' energy metabolism, with a specific focus on comparing abnormalities between tumor and normal cells, as well as summarizing potential targets for tumor therapy. Additionally, this review also elucidates the aberrant mechanisms underlying four major energy metabolic pathways (glucose, lipid, glutamine, and mitochondria-dependent) during carcinogenesis and tumor progression. Through the utilization of graphical representations, we have identified anomalies in crucial energy metabolism pathways, encompassing transporter proteins (glucose transporter, CD36, and ASCT2), signaling molecules (Ras, AMPK, and PTEN), as well as transcription factors (Myc, HIF-1α, CREB-1, and p53). The key molecules responsible for aberrant energy metabolism in tumors may serve as potential targets for cancer therapy. Therefore, this review provides an overview of the distinct energy-generating pathways within tumor cells, laying the groundwork for developing innovative strategies for precise cancer treatment.</p>","PeriodicalId":12700,"journal":{"name":"Genes, Chromosomes & Cancer","volume":"63 11","pages":""},"PeriodicalIF":3.1,"publicationDate":"2024-11-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/gcc.70008","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142708377","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}