Cancer letters最新文献

{"title":"RNA methyltransferase METTL16: from molecular mechanisms to therapeutic prospects in cancers.","authors":"Zhaohu Shi, Xiankui Cao, Yiming Ma, Kaiqiang Li, Xin Wang, Jie Lin, Hailin Tang, Xudong Zhu","doi":"10.1016/j.canlet.2025.217698","DOIUrl":"https://doi.org/10.1016/j.canlet.2025.217698","url":null,"abstract":"<p><p>Methyltransferase-like 16 (METTL16) plays a critical role in epigenetic regulation, particularly through RNA methylation. As a key RNA methyltransferase, METTL16 catalyzes the addition of N6-methyladenosine modifications to RNA molecules, which are essential for the regulation of RNA stability, post-transcriptional modifications, and translation efficiency. This, in turn, links METTL16-mediated gene expression to various diseases. Notably, METTL16 has dual regulatory effects on tumors, with its influence varying according to the specific cancer type. Furthermore, METTL16 expression and activity are tightly controlled through multiple layers, including transcriptional regulation, epigenetic modifications (such as DNA methylation and histone modifications), and signaling pathways associated with hypoxia, particularly hypoxia-inducible factors. These regulatory networks collectively govern METTL16's function, impacting tumor progression, development, and drug resistance. Targeting METTL16 with small molecule inhibitors or activators offers a promising therapeutic strategy for cancer treatment. The potential of METTL16 as a therapeutic target is further enhanced when combined with other treatment modalities. Future research should aim to elucidate the specific pathophysiological mechanisms of METTL16 across various cancer types, evaluate its therapeutic potential, and develop compounds capable of inhibiting or activating METTL16. This review consolidates the current understanding of METTL16, emphasizing its expression patterns, functional roles, regulatory mechanisms, and therapeutic prospects in cancers.</p>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":" ","pages":"217698"},"PeriodicalIF":9.1,"publicationDate":"2025-04-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143802608","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":"Pharmacological and therapeutic innovation to mitigate radiation-induced cognitive decline (RICD) in brain tumor patients","authors":"Jemema Agnes Tripena Raj,&nbsp;Janmey Shah,&nbsp;Shubham Ghanekar,&nbsp;Geofrey John,&nbsp;Jayant S. Goda ,&nbsp;Abhishek Chatterjee","doi":"10.1016/j.canlet.2025.217700","DOIUrl":"10.1016/j.canlet.2025.217700","url":null,"abstract":"<div><div>Radiation therapy is a key treatment modality in both primary and metastatic brain tumors. However, despite its efficacy, it often results in cognitive decline, particularly after whole brain RT (WBRT). Radiation-induced cognitive impairment, which affects memory, attention, and executive function, significantly affects Quality Of Life (QOL) and functional independence. Although white matter necrosis, a hallmark of conventional radiation techniques, has become less common with modern methods, cognitive deficits remain a persistent issue. Neuroinflammation is a key driver of this decline, along with disruptions in hippocampal neurogenesis and damage to regions of the brain. Radiation affects neural stem cells, mature neurons, and glial cells, particularly within the hippocampus, affecting cognition. Recent studies suggest that targeting neuroinflammation and other key Signaling pathways (NMDAR, RAAS, PARP, PPAR, etc.) can reduce cognitive impairment. This review examines the theme of radiation-induced cognitive decline and explores possible interventions to prevent or mitigate these outcomes.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"620 ","pages":"Article 217700"},"PeriodicalIF":9.1,"publicationDate":"2025-04-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143800441","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":"Intersection between lung cancer and neuroscience: opportunities and challenges.","authors":"Xiang Xiao, Lingli Huang, Ming Li, Quanli Zhang","doi":"10.1016/j.canlet.2025.217701","DOIUrl":"https://doi.org/10.1016/j.canlet.2025.217701","url":null,"abstract":"<p><p>Lung cancer, which has the highest morbidity and mortality rates worldwide, involves intricate interactions with the nervous system. Research indicates that the nervous system not only plays a role in the origin of lung cancer, but also engages in complex interactions with cancer cells through neurons, neurotransmitters, and various neuroactive molecules during tumor proliferation, invasion, and metastasis, especially in brain metastases. Cancer and its therapies can remodel the nervous system. Despite advancements in immunotherapy and targeted therapies in recent years, drug resistance of lung cancer cells after treatment limits improvements in patient survival and prognosis. The emergence of neuroscience has created new opportunities for the treatment of lung cancer. However, it also presents challenges. This review emphasizes that a deeper understanding of the interactions between the nervous system and lung cancer, along with the identification of new therapeutic targets, may lead to significant advancements or even a revolution in treatment strategies for patients with lung cancer.</p>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":" ","pages":"217701"},"PeriodicalIF":9.1,"publicationDate":"2025-04-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143802606","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":"Glutathione Metabolism in Ferroptosis and Cancer Therapy.","authors":"Xiangfei Xue, Manyuan Wang, Jiangtao Cui, Minying Yang, Lifang Ma, Rui Kang, Daolin Tang, Jiayi Wang","doi":"10.1016/j.canlet.2025.217697","DOIUrl":"https://doi.org/10.1016/j.canlet.2025.217697","url":null,"abstract":"<p><p>Glutathione (GSH), a non-enzymatic antioxidant in mammalian cells, plays an essential role in maintaining redox balance, mitigating oxidative stress, and preserving cellular homeostasis. Beyond its well-established function in detoxifying reactive oxygen species (ROS), GSH serves as a critical regulator of ferroptosis-an iron-dependent form of cell death marked by excessive lipid peroxidation. Serving as a cofactor for glutathione peroxidase 4 (GPX4), GSH catalyzes the conversion of lipid peroxides into non-toxic lipid alcohols, thereby preventing the accumulation of deleterious lipid oxidation products and halting the spread of oxidative damage. In cancer cells, upregulated GSH synthesis and GPX4 activity contribute to an enhanced antioxidant defense, countering oxidative stress provoked by increased metabolic demands and exposure to therapeutic agents such as chemotherapy, radiotherapy, and immunotherapy. This ability of cancer cells to modulate their ferroptosis susceptibility through GSH metabolism underscores its potential as a therapeutic target. Additionally, GSH influences several key oncogenic and tumor-suppressive signaling pathways, including NFE2L2/NRF2, TP53/p53, NF-κB, Hippo, and mTOR, which collectively regulate responses to oxidative stress, affect metabolic processes, and modulate sensitivity to ferroptosis in cancer cells. This review explores recent advancements in understanding GSH's multifaceted role in ferroptosis, emphasizing its implications for cancer biology and therapeutic interventions.</p>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":" ","pages":"217697"},"PeriodicalIF":9.1,"publicationDate":"2025-04-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143794518","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":"KAP1 promotes gastric adenocarcinoma progression by activating Hippo/YAP1 signaling via binding to HNRNPAB.","authors":"Shumei Song, Yibo Fan, Gengyi Zou, Longfei Huo, Janani Kumar, Yuan Li, Ruiping Wang, Enyu Dai, Jiankang Jin, Ailing W Scott, Shan Shao, Melissa Pool Pizzi, Jody V Vykoukal, Hiryuki Katayama, Samir Hanash, George A Calin, Xing Zhang, Min Gyu Lee, Zhenning Wang, Yuan-Hung Lo, Qiong Gan, Rebecca E Waters, Feng Yin, Linghua Wang, Xiaodong Cheng, Jaffer A Ajani, Shilpa S Dhar","doi":"10.1016/j.canlet.2025.217695","DOIUrl":"https://doi.org/10.1016/j.canlet.2025.217695","url":null,"abstract":"<p><p>Gastric adenocarcinoma (GAC) remains a significant global health challenge, with over a million new cases annually. Peritoneal carcinomatosis (PC), detected in ∼20% of cases at diagnosis and ∼45% later, is uniformly fatal, with limited treatment options. This study investigated the role of KAP1 in GAC progression, focusing on its interaction with YAP1 and cancer stemness traits. Analysis of over 596 primary GACs and 72 PC samples revealed that high nuclear KAP1 expression correlates with poor prognosis. KAP1 knockdown reduced oncogenic activity and stemness traits in GAC cells. Mechanistically, KAP1 positively regulates YAP1 transcription by binding to its promoter and reducing H3K27ac levels. Mass spectrometry identified an interaction between KAP1 and HNRNPAB, further modulating YAP1 signaling. Expression of the KRAB domain of ZFP568 without its DNA-binding zinc fingers inhibited both KAP1 and YAP1 expression, significantly reducing colony formation and tumor growth in vivo. Additionally, emerging antisense oligonucleotides (ASOs) targeting KAP1 or YAP1 effectively suppressed mouse tumor progression. These findings establish KAP1 as a critical driver of tumor progression in GAC through YAP1 regulation and HNRNPAB interaction, highlighting its potential therapeutic target. This study advances our understanding and offers a preclinical framework to improve outcomes for GAC.</p>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":" ","pages":"217695"},"PeriodicalIF":9.1,"publicationDate":"2025-04-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143794524","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":"Ferroptosis meets inflammation: A new frontier in cancer therapy","authors":"Hu Liu ,&nbsp;Hui Xue ,&nbsp;Qian Guo ,&nbsp;Xutong Xue ,&nbsp;Lixue Yang ,&nbsp;Kaijun Zhao ,&nbsp;Yu'e Liu","doi":"10.1016/j.canlet.2025.217696","DOIUrl":"10.1016/j.canlet.2025.217696","url":null,"abstract":"<div><div>Ferroptosis, an iron-dependent form of regulated cell death driven by lipid peroxidation, has emerged as a critical player in cancer pathogenesis. Concurrently, inflammation, a key biological response to tissue injury or infection, significantly influences cancer development and progression. The interplay between ferroptosis and inflammation represents a promising yet underexplored area of research. This review synthesizes recent advances in understanding the molecular mechanisms governing their interaction, emphasizing how ferroptosis triggers inflammatory responses and how inflammatory mediators, such as TNF-α, regulate ferroptosis through iron metabolism and lipid peroxidation pathways. Key molecular targets within the ferroptosis-inflammation axis, including GPX4, ACSL4, and the NF-κB signaling pathway, offer therapeutic potential for cancer treatment. By modulating these targets, it may be possible to enhance ferroptosis and fine-tune inflammatory responses, thereby improving therapeutic outcomes. Additionally, this review explores the broader implications of targeting the ferroptosis-inflammation interplay in disease treatment, highlighting opportunities for developing innovative strategies to combat cancer. By bridging the gap in current knowledge, this review provides a comprehensive resource for researchers and clinicians, offering insights into the therapeutic potential of this intricate biological relationship.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"620 ","pages":"Article 217696"},"PeriodicalIF":9.1,"publicationDate":"2025-04-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143791327","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":"Gap-App: A Sex-Distinct AI-Based Predictor for Pancreatic Ductal Adenocarcinoma Survival as A Web Application Open to Patients and Physicians.","authors":"Anuj Ojha, Shu-Jun Zhao, Basil Akpunonu, Jian-Ting Zhang, Kerri A Simo, Jing-Yuan Liu","doi":"10.1016/j.canlet.2025.217689","DOIUrl":"https://doi.org/10.1016/j.canlet.2025.217689","url":null,"abstract":"<p><p>In this study, using RNA-Seq gene expression data and advanced machine learning techniques, we identified distinct gene expression profiles between male and female pancreatic ductal adenocarcinoma (PDAC) patients. Building on this insight, we developed sex-specific 3-year survival predictive models alongside a single comprehensive model. Despite smaller sample sizes, the sex-specific models outperformed the general model. We further refined our models by selecting the most important features from the initial models. The refined sex-specific predictive models achieved higher accuracy and consistently outperformed the refined comprehensive model, highlighting the value of sex-specific analysis. To ensure robustness, all refined sex-specific models were calibrated and evaluated using an independent dataset. Random Forest models emerged as the most effective predictors, achieving accuracies of 90.33% for males and 90.40% for females on the training dataset, and 81.25% for males and 89.47% for females on the independent test dataset. These top-performing models were integrated into Gap-App, a web application that leverages individual gene expression profiles and sex information for personalized survival predictions. As the first online tool bridging complex genomic data with clinical application, Gap-App facilitates more precise, individualized cancer care, marking a significant step in personalized prognosis prediction. This study underscores the importance of incorporating sex differences in predictive modeling and sets the stage for the shift from traditional one-size-fits-all to more personalized and targeted medicine. The Gap-App service is freely available for patients and clinicians at www.gap-app.org.</p>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":" ","pages":"217689"},"PeriodicalIF":9.1,"publicationDate":"2025-04-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143794514","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":"TRAIL induces cytokine production via the NFkB2 pathway promoting neutrophil chemotaxis and neutrophil-mediated immune-suppression in triple negative breast cancer cells","authors":"Manjari Kundu ,&nbsp;Yoshimi E. Greer ,&nbsp;Alexei Lobanov ,&nbsp;Lisa Ridnour ,&nbsp;Renee N. Donahue ,&nbsp;Yeap Ng ,&nbsp;Shashi Ratnayake ,&nbsp;Karley White ,&nbsp;Donna Voeller ,&nbsp;Sarah Weltz ,&nbsp;Qingrong Chen ,&nbsp;Stephen J. Lockett ,&nbsp;Maggie Cam ,&nbsp;Daoud Meerzaman ,&nbsp;David A. Wink ,&nbsp;Roberto Weigert ,&nbsp;Stanley Lipkowitz","doi":"10.1016/j.canlet.2025.217692","DOIUrl":"10.1016/j.canlet.2025.217692","url":null,"abstract":"<div><div>Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a potential cancer therapeutic that induces apoptosis in cancer cells while sparing the non-malignant cells in preclinical models. However, its efficacy in clinical trials has been limited, suggesting unknown mechanisms modulating TRAIL activity in patients. We hypothesized that TRAIL treatment elicits transcriptional changes in triple negative breast cancer (TNBC) cells that alter the immune milieu. RNAseq analysis of MDA-MB-231 cells along with validation in additional cell lines demonstrated that TRAIL induced cytokines such as CXCLs 1, 2, 3, 8,11 and IL-6, which are known to modify neutrophil function. Mechanistically, TRAIL dependent induction of the cytokines was predominantly mediated by death receptor 5, caspase-8 and the non-canonical NFKB2 pathway. These cytokines produced by TRAIL-treated TNBC cells enhanced chemotaxis of normal human donor isolated neutrophils. Using TNBC xenograft models<em>,</em> TRAIL induced activation of NFkB2 pathway, cytokine production and increased neutrophil recruitment into the tumors. Moreover, preincubation of neutrophils in supernatants from TRAIL-treated TNBC cells significantly impaired neutrophil function as measured by reduced respiratory burst and cytotoxic effect against TNBC cells. Transcriptomic analysis of neutrophils incubated with either TRAIL alone or supernatant of TRAIL-treated TNBC cells revealed increased expression of inflammatory cytokines, immune modulatory genes, immune checkpoint genes, and genes implicated in delayed neutrophil apoptosis. Functional studies showed that these neutrophils suppress T cell proliferation and augment Treg suppressive phenotype. Collectively, our study demonstrates a novel role of TRAIL-induced NFKB2-dependent cytokine production that promotes neutrophil chemotaxis and neutrophil- mediated immune suppression.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"620 ","pages":"Article 217692"},"PeriodicalIF":9.1,"publicationDate":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143787978","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":"Mitigating ambient RNA and doublets effects on single cell transcriptomics analysis in cancer research","authors":"Madhu Sudhana Saddala ,&nbsp;Midhuna Sree Chittineni ,&nbsp;Niharitha Hariharan ,&nbsp;Anijah L. Rias ,&nbsp;Ganji Purnachandra Nagaraju","doi":"10.1016/j.canlet.2025.217693","DOIUrl":"10.1016/j.canlet.2025.217693","url":null,"abstract":"<div><div>In cancer biology, where understanding the tumor microenvironment at high resolution is vital, ambient RNA contamination becomes a considerable problem. This hinders accurate delineation of intratumoral heterogeneity, complicates the identification of potential biomarkers, and decelerates advancements in precision oncology. To solve this problem, several computational approaches are created to determine the ambient RNA contribution from scRNA-seq datasets. Techniques like SoupX and DecontX assist in assessing and eliminating ambient RNA contamination from primary gene expression profiles. Practical solutions like CellBender employ deep learning techniques to concurrently address ambient RNA contamination and background noise, offering a contemporary end-to-end strategy for data preparation. This high-quality, reliable data enables clinicians and researchers to make effective decisions that will help ensure interventions are rooted in reproducible evidence, giving hope for developing more effective targeted therapies.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"620 ","pages":"Article 217693"},"PeriodicalIF":9.1,"publicationDate":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143787972","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":"MK2 promotes p16 negative head and neck cancer migration, invasion, and metastasis.","authors":"Deri Morgan, Dakota Dd Okwuone, Kiersten L Berggren, Levi Arnold, Alyssa Schmidt, Colby Spiess, Hannah Smith, Ravi Yada, Nathan Hendrikse, Rashna Madan, Devin Shrock, Chris Lominska, Mengjia Hu, Malgorzata Witek, Steven Soper, Yuting Lin, Hao Gao, Dennis J McCance, Sufi M Thomas, David Beebe, Sheena C Kerr, Gregory N Gan","doi":"10.1016/j.canlet.2025.217690","DOIUrl":"https://doi.org/10.1016/j.canlet.2025.217690","url":null,"abstract":"<p><p>For patients with locally advanced, p16-negative head and neck squamous cell carcinoma (HNSCC), overall survival remains poor due to primary locoregional failure and distant metastasis following curative therapy. We aimed to understand how MAPKAPK2 (MK2) regulates HNSCC tumor cell migration and invasion, important first steps in cancer metastases. The TCGA database and HNSCC tissue microarrays were used to show that MK2 expression was associated with more advanced cancers and faster cancer recurrence rates. We observed that silencing of tumor MK2 in human cell lines (shRNA) caused a significant reduction in tumor cell migration-invasion in a complex HNSCC microphysiologic system used to recapitulate the tumor microenvironment. Murine cells (Ly2) with MK2 silenced (CRISPR-Cas9) also demonstrated reduced migration and invasion using 2D and 3D monoculture cell migration-invasions assays. Ly2 cells are orthotopic p16-negative murine metastatic cells that spontaneously metastasize, and we observed that MK2 inhibition via genetic (Cas9/CRISPR) or pharmacologic (PF-3644022) methods led to a significant reduction in the number of circulating tumor cells, fewer lymph node and lung metastases, and MK2 inhibited mice showed improved overall survival. Our findings suggest that HNSCC MK2 regulates tumor cell migration-invasion and may be a promising therapeutic target to reduce metastases.</p>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":" ","pages":"217690"},"PeriodicalIF":9.1,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143787973","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}