Cancer letters最新文献

{"title":"Increased phosphorylation of AMPKα1 S485 in colorectal cancer and identification of PKCα as a responsible kinase.","authors":"Yan Zhou, Tingting Lei, Zhimin Tang, Pei Guo, Deqiang Huang, Zhijun Luo, Linyu Luo","doi":"10.1016/j.canlet.2024.217418","DOIUrl":"10.1016/j.canlet.2024.217418","url":null,"abstract":"<p><p>The present study attempts to examine the biological effect of phosphorylation of AMPKα1 S485 and identify the responsible kinase in colon cancer cells. Thus, our results showed that S485 phosphorylation was increased in colorectal cancer specimens as compared with adjacent normal tissues, which was inversely correlated to phosphorylation of T172. Our study further revealed that phosphorylation of S485 on AMPKα1 plays a promoting role in cell proliferation, colony formation, migration and growth of Xenograft tumor. Furthermore, we identified PKCα as a kinase specific for phosphorylation of S485. First, under the basal condition, S485 phosphorylation was blunted by Gö6983, a pan PKC inhibitor, but not by Akt inhibitor, MK2206, although the latter countered off the insulin-stimulated phosphorylation. Second, the phosphorylation was enhanced by PMA and attenuated by sgRNA for PKCα, but not by PKCγ and PKCδ, neither by siRNA for Akt1. Third, the phosphorylation was suppressed by shRNA for PLCγ1. Fourth, the phosphorylation was enhanced by ectopically expressing a constitutively active mutant of PKCα, but not PKCγ. Finally, the increase of S485 phosphorylation by high glucose or palmitic acid was almost completely abolished by Gö6983. Altogether, our data reinforced the tumor suppressive function of AMPK and demonstrated that PKCα is a major kinase responsible for phosphorylation of S485, which contributes to one of the mechanisms underlying the regulation of AMPK in cancer cells in response to nutritional conditions.</p>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":" ","pages":"217418"},"PeriodicalIF":9.1,"publicationDate":"2024-12-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142892295","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":"Nervous system in colorectal cancer.","authors":"Chunjie Xu, Chunhui Jiang, Yuan Tian, Ye Liu, Hao Zhang, Zeyu Xiang, Hanbing Xue, Lei Gu, Qing Xu","doi":"10.1016/j.canlet.2024.217431","DOIUrl":"10.1016/j.canlet.2024.217431","url":null,"abstract":"<p><p>A malignant tumor is a complex systemic disease involving the nervous system, which regulates nerve signals. Cancer neuroscience is a field that explores the interactions between tumors and the nervous system. The gastrointestinal tract is a typical peripheral organ with abundant neuroregulation and is regulated by the peripheral, enteric, and central nervous systems (PNS, ENS, and CNS, respectively). The physiological functions of the gastrointestinal tract are maintained via complex neuromodulation. Neuroregulatory imbalance is the primary cause of gastrointestinal diseases, including colorectal cancer (CRC). In CRC, there is a direct interaction between the nervous system and tumor cells. Moreover, this tumor-nerve interaction can indirectly regulate the tumor microenvironment, including the microbiota, immunity, and metabolism. In addition to the lower nerve centers, the stress response, emotion, and cognition represented by the higher nerve centers also participate in the occurrence and progression of CRC. Herein, we review some basic knowledge regarding cancer neuroscience and elucidate the mechanism underlying tumor-nerve interactions in CRC.</p>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":" ","pages":"217431"},"PeriodicalIF":9.1,"publicationDate":"2024-12-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142892313","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":"Sulforaphane potentiates the efficacy of chemoradiotherapy in glioblastoma by selectively targeting thioredoxin reductase 1.","authors":"Yuqian Ge, Zehe Ge, Fuwei Tian, Xiaoyu Tai, Dongyin Chen, Shuhong Sun, Zhumei Shi, Jianxing Yin, Guining Wei, Dongmei Li, Lude Wang, Wenxia Xu, Minfeng Tong, Fang Liu, Lin Zhao, Xu Qian, Xin Ge","doi":"10.1016/j.canlet.2024.217429","DOIUrl":"10.1016/j.canlet.2024.217429","url":null,"abstract":"<p><p>Chemoradiotherapy is a conventional treatment modality for patients with glioblastoma (GBM). However, the efficacy of this approach is significantly hindered by the development of therapeutic resistance. The thioredoxin system, which plays a crucial role in maintaining redox homeostasis, confers protection to cancer cells against apoptosis induced by chemoradiotherapy. Herein, we demonstrate that sulforaphane (SFN), an isothiocyanate phytochemical with anti-cancer effects, inhibits the activity of thioredoxin reductase 1 (TrxR1) through covalent conjugation with residues C59/64/497&U498. This inhibition of TrxR1 leads to the accumulation of reactive oxygen species (ROS), thereby enhancing chemoradiotherapy-induced apoptosis in GBM cells. Furthermore, SFN-induced ROS accumulation facilitates the polarization of M1-like macrophages, which synergistically sensitize GBM tumors to chemoradiotherapy. In conclusion, our study unveils that SFN has potential benefits in improving the effect of chemoradiotherapy and prognosis for GBM patients by targeting TrxR1.</p>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":" ","pages":"217429"},"PeriodicalIF":9.1,"publicationDate":"2024-12-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142892321","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":"Driver mutation landscape of acute myeloid leukemia provides insights for neoantigen-based immunotherapy.","authors":"Peng Jin, Jie Shen, Ming Zhao, Jinyi Yu, Wen Jin, Ge Jiang, Zeyi Li, Mengke He, Xiaxin Liu, Shishuang Wu, Fangyi Dong, Yuncan Cao, Hongming Zhu, Xiaoyang Li, Xiaoling Wang, Yunxiang Zhang, Zhen Jin, Kankan Wang, Junmin Li","doi":"10.1016/j.canlet.2024.217427","DOIUrl":"https://doi.org/10.1016/j.canlet.2024.217427","url":null,"abstract":"<p><p>Acute myeloid leukemia (AML) has lagged in benefiting from immunotherapies, primarily due to the scarcity of actionable AML-specific antigens. Driver mutations represent promising immunogenic targets, but a comprehensive characterization of the AML neoantigen landscape and their impact on patient outcomes and the AML immune microenvironment remain unclear. Herein, we conducted matched DNA and RNA sequencing on 304 AML patients and extensively integrated data from additional ∼2,500 AML cases, identifying 49 driver genes, notably characterized by a significant proportion of insertions and deletions (indels). Neoantigen analysis showed that indels triggered a higher abundance of neoantigens both in quantity and quality compared to single nucleotide variants (SNVs) and gene fusions. By integrating peptide features pertinent to neoantigen presentation and T cell recognition, we developed two robust models of epitope immunogenicity that significantly enriched immunogenic neoepitopes. We validated 30 neoantigens through in vitro direct binding assays of predicted peptides to MHC proteins and confirmed the immunogenicity of 20 neoantigens using interferon-γ ELISpot and tetramer assays. Moreover, we demonstrated that patients with higher neoantigen loads, derived from driver mutations, exhibited poor clinical outcomes and an IFN-driven adaptive immune response, which was associated with immune suppression and tumor evasion. Through deconvolution of large-scale bulk transcriptomes, integration of single-cell RNA sequencing and multiparametric flow cytometry, we confirmed a strong association between neoantigen load and CD8⁺ T cell exhaustion. This study provides a comprehensive landscape of AML neoantigens derived from driver mutations, offering putative immunogenic targets and emphasizing the need for strategies to revitalize the immunosuppressive milieu.</p>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":" ","pages":"217427"},"PeriodicalIF":9.1,"publicationDate":"2024-12-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142892288","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":"Tumor metastasis and recurrence: The role of perioperative NETosis.","authors":"Fu Zeng, Yuwen Shao, Jingyi Wu, Jingwen Luo, Ying Yue, Yang Shen, Yanghanzhao Wang, Yuxin Shi, Dan Wu, Juan P Cata, Shuofei Yang, Hao Zhang, Changhong Miao","doi":"10.1016/j.canlet.2024.217413","DOIUrl":"https://doi.org/10.1016/j.canlet.2024.217413","url":null,"abstract":"<p><p>Although surgical resection of tumor mass remains the mainstay of curative therapeutic management for solid tumors, accumulating studies suggest that these procedures promote tumor recurrence and metastasis. Regarded as the first immune cells to fight against infectious or inflammatory insults from surgery, neutrophils along with their ability of neutrophil extracellular traps (NETs) production has attracted much attention. A growing body of evidence suggests that NETs promote cancer metastasis by stimulating various stages, including local invasion, colonization, and growth. Therefore, we discussed the mechanism of NETosis induced by surgical stress and tumor cells, and the contribution of NETs on tumor metastasis: aid in the tumor cell migration and proliferation, evasion of immune surveillance, circulating tumor cell adhesion and establishment of a metastatic niche. Lastly, we summarized existing NET-targeting interventions, offering recent insights into potential targets for clinical intervention.</p>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"611 ","pages":"217413"},"PeriodicalIF":9.1,"publicationDate":"2024-12-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142892282","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":"TIM3 on natural killer cells regulates antibody-dependent cellular cytotoxicity in HER2-positive gastric cancer.","authors":"Chikanori Tsutsumi, Kenoki Ohuchida, Hirono Tsutsumi, Yuki Shimada, Yutaka Yamada, Kiwa Son, Sayuri Hayashida, Naoki Katayama, Yuki Mochida, Chika Iwamoto, Nobuhiro Torata, Kohei Horioka, Koji Shindo, Yusuke Mizuuchi, Naoki Ikenaga, Kohei Nakata, Keiichi Ota, Eiji Iwama, Masami Yamamoto, Tetsuya Tsukamoto, Sachiyo Nomura, Takashi Morisaki, Yoshinao Oda, Isamu Okamoto, Masafumi Nakamura","doi":"10.1016/j.canlet.2024.217412","DOIUrl":"https://doi.org/10.1016/j.canlet.2024.217412","url":null,"abstract":"<p><p>Therapies targeting HER2 are the standard treatment for HER2-positive gastric cancer (GC). Trastuzumab, a monoclonal antibody against HER2, exerts anti-tumor activity through cell growth regulation and antibody-dependent cellular cytotoxicity (ADCC). ADCC is induced by the binding of trastuzumab to Fcγ receptor III (CD16) in natural killer (NK) cells. However, the relationship between immune checkpoint (IC) molecules of NK cells and trastuzumab-induced ADCC is poorly understood. We performed single-cell RNA sequencing (scRNA-seq) and immunohistochemistry to identify IC molecules associated with CD16 expression in NK cells of GC patients. Additionally, we conducted in vitro assays with HER2-transfected GC cells and in vivo experiments using a mouse HER2-positive GC model to assess expression changes in IC molecules in NK cells and their ligands during trastuzumab treatment. In GC patients, the expression of TIM3, an IC molecule, was strongly correlated with that of CD16 in NK cells. In vitro assays showed that ADCC with trastuzumab increased TIM3 expression in NK cells. scRNA-seq analysis revealed that TIM3 expression of cytotoxic NK cells was elevated in HER2-positive GC patients treated with trastuzumab. HMGB1, a TIM3 ligand, was expressed at higher levels in HER2-transfected GC cells than in controls. Furthermore, HMGB1 expression was higher in HER2-positive GC patients treated with trastuzumab compared to untreated HER2-positive GC patients. In the mouse HER2-positive GC model, anti-TIM3 antibodies and trastuzumab demonstrated synergistic anti-tumor effects without toxicity. This study suggests the combined anti-TIM3 antibody and trastuzumab therapy may have potential as a new treatment strategy for HER2-positive GC.</p>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"611 ","pages":"217412"},"PeriodicalIF":9.1,"publicationDate":"2024-12-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142892279","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":"WEE1 confers resistance to KRAS^G12C inhibitors in non-small cell lung cancer.","authors":"Gaku Yamamoto, Kosuke Tanaka, Ryo Kamata, Hitoshi Saito, Tomoko Yamamori-Morita, Takehiro Nakao, Jie Liu, Shunta Mori, Shigehiro Yagishita, Akinobu Hamada, Yuki Shinno, Tatsuya Yoshida, Hidehito Horinouchi, Yuichiro Ohe, Shun-Ichi Watanabe, Yasushi Yatabe, Hidenori Kitai, Satoshi Konno, Susumu S Kobayashi, Akihiro Ohashi","doi":"10.1016/j.canlet.2024.217414","DOIUrl":"10.1016/j.canlet.2024.217414","url":null,"abstract":"<p><p>KRAS^G12C inhibitors sotorasib and adagrasib have been approved for the treatment of KRAS^G12C-mutant non-small cell lung cancer (NSCLC). However, the efficacy of single-agent treatments is limited, presumably due to multiple resistance mechanisms. To overcome these therapeutic limitations, combination strategies that potentiate the antitumor efficacy of KRAS^G12C inhibitors must be developed. Through unbiased high-throughput screening of 1395 kinase inhibitors, we identified adavosertib, a WEE1 inhibitor, as a promising combination partner of sotorasib. The combination of sotorasib and adavosertib exhibited synergistic antiproliferative activities both in vitro and in vivo, irrespective of TP53, STK11, and KEAP1 co-mutation profiles. WEE1 inhibition potentiated MCL-1-mediated apoptosis in sotorasib-treated cancer cells. Mechanistically, the combination downregulated MCL-1 protein levels by attenuating de novo translation and enhancing its degradation. WEE1 overexpression conferred resistance against sotorasib via MCL-1 upregulation. Moreover, cells that acquired sotorasib resistance profoundly upregulated both WEE1 and MCL-1 proteins, highlighting WEE1 as a crucial driver of sotorasib resistance. Importantly, WEE1 inhibition re-sensitized resistant cells to sotorasib treatment. The current findings demonstrate that combined inhibition of KRAS^G12C and WEE1 not only exhibits synergistic antitumor efficacy but also overcomes resistance to KRAS^G12C inhibitors, thus representing a novel therapeutic strategy for KRAS^G12C-mutant NSCLC.</p>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":" ","pages":"217414"},"PeriodicalIF":9.1,"publicationDate":"2024-12-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142892326","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":"A mechanistic, functional, and clinical perspective on targeting CD70 in cancer.","authors":"Sandeep Kumar, Sowdhamini Mahendiran, Rakesh Sathish Nair, Harsh Vyas, Sunil Kumar Singh, Piush Srivastava, Saket Jha, Basabi Rana, Ajay Rana","doi":"10.1016/j.canlet.2024.217428","DOIUrl":"10.1016/j.canlet.2024.217428","url":null,"abstract":"<p><p>The oncoimmunology research has witnessed notable advancements in recent years. Reshaping the tumor microenvironment (TME) approach is an effective method to improve antitumor immune response. The T cell-mediated antitumor response is crucial for favorable therapeutic outcomes in several cancers. The United States Food and Drug Administration (FDA) has approved immune checkpoint inhibitors (ICIs) for targeting the immune checkpoint proteins (ICPs) expressed in various hematological and solid malignancies. The ICPs are T cell co-inhibitory molecules that block T cell activation and, thus, antitumor response. Currently, most of the FDA-approved ICIs are antagonistic antibodies of programmed death-ligand 1 (PD-L1), programmed cell death protein 1 (PD-1), and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4). In contrast to ICPs, the T cell costimulatory molecules are required for T cell activation, expansion, and effector function. However, the abrupt expression of these costimulatory molecules in tumors presents a concern for T cell-mediated antitumor response. One of the T cell costimulatory molecules, the cluster of differentiation 70 (CD70), has emerged as a druggable target in various hematological and solid malignancies due to its role in T cell effector function and immune evasion. The present review describes the expression of CD70, factors affecting the CD70 expression, the physiological and clinical relevance of CD70, and the current approaches to target CD70 in hematological and solid malignancies.</p>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":" ","pages":"217428"},"PeriodicalIF":9.1,"publicationDate":"2024-12-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142892266","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":"m6A demethylation of NNMT in CAFs promotes gastric cancer progression by enhancing macrophage M2 polarization.","authors":"Tsz Kin Mak, Kuan Li, Zidan Zhao, Kexin Wang, Leli Zeng, Qilang He, Weiqun Lu, Wei Chen, Yulong He, Jia Li, Changhua Zhang","doi":"10.1016/j.canlet.2024.217422","DOIUrl":"https://doi.org/10.1016/j.canlet.2024.217422","url":null,"abstract":"<p><p>Cancer associated fibroblasts (CAFs) are the predominant stromal cells in the tumor microenvironment of gastric cancer (GC), interacting with both immune and tumor cells to drive cancer progression. However, the precise link between these interactions and their potential as therapeutic targets remains poorly understood. In this study, we identified for the first time that nicotinamide N-methyltransferase (NNMT) derived from CAFs promoted M2 macrophage polarization, which, in turn, facilitated the proliferation and migration of GC cells. Additionally, we discovered that NNMT expression in CAFs was regulated by the Fat mass and obesity related protein (FTO) via m6A demethylation. Both NNMT and FTO were highly expressed in tumor tissues and CAFs, with a positive correlation between FTO and NNMT levels in clinical samples. Mechanistically, FTO bound to NNMT mRNA, reducing m6A modification and enhancing NNMT expression. Knockdown of either NNMT or FTO in CAFs effectively inhibited M2 macrophage polarization and suppressed GC progression. These findings were validated in patient-derived organoid models and nude mouse models of GC. Collectively, our data revealed that FTO promoted M2 macrophage polarization by regulating the m6A demethylation of NNMT in CAFs, thereby driving GC progression. This identified a potential novel target for GC diagnosis and therapy.</p>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":" ","pages":"217422"},"PeriodicalIF":9.1,"publicationDate":"2024-12-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142892306","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":"Neutrophils in cancer drug resistance: Roles and therapeutic opportunities.","authors":"Hao Liu, Hongyu Zhao, Mingzhen Zhou, Xiaodi Zhao, Yuanyuan Lu","doi":"10.1016/j.canlet.2024.217417","DOIUrl":"https://doi.org/10.1016/j.canlet.2024.217417","url":null,"abstract":"<p><p>The tumor microenvironment (TME) is closely associated with the therapeutic response and clinical outcome of cancer drug therapies, which mainly include immunotherapy, chemotherapy and targeted therapy. Neutrophils that infiltrate tumors, also known as tumor-associated neutrophils (TANs), constitute a primary part of the TME. However, the functional importance of TANs in cancer drug therapy has long been overlooked because of their relatively short life span. Recent studies have shown that TANs play crucial protumoral or antitumoral roles in cancer drug treatment, largely because of their diversity and plasticity. This review describes the development, heterogeneity and recruitment of neutrophils in the context of cancer and emphasizes the role and mechanisms of TANs in cancer drug resistance. Additionally, several potential neutrophil-targeted strategies are discussed.</p>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"611 ","pages":"217417"},"PeriodicalIF":9.1,"publicationDate":"2024-12-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142892275","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}