International journal of oncology最新文献

{"title":"Application of cfDNA methylation in cancer prognostic assessment: Progress and challenges (Review).","authors":"Chenxi Su, Jiaqi Wu, Liping Jiang, Tongtong Lv, Wenxi Liu, Jintong Zhang, Yanhua Zhang, Xiaochun Peng, Jie Tan","doi":"10.3892/ijo.2025.5804","DOIUrl":"10.3892/ijo.2025.5804","url":null,"abstract":"<p><p>Cancer prognostic assessment constitutes an essential component of cancer treatment and management. It encompasses the prediction of patients' disease progression, treatment effect and survival. Circulating free DNA (cfDNA) refers to highly fragmented DNA that exists extracellularly in the human bloodstream. Its methylation status is not only a reliable indicator for the prognosis of cancer, but also a highly accurate predictor of the prognosis of cancer. As an emerging non‑invasive biomarker, cfDNA has demonstrated considerable potential in cancer prognostic assessment in recent years. The present review provided a comprehensive review of the promising applications of cfDNA methylation in cancer prognostic assessment, while also discussing the challenges that must be addressed to fully realize its clinical potential. As technology advances and research deepens, cfDNA methylation is expected to play an increasingly pivotal role in the field of cancer precision medicine.</p>","PeriodicalId":14175,"journal":{"name":"International journal of oncology","volume":"67 6","pages":""},"PeriodicalIF":4.9,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145148894","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"[Expression of Concern] miR‑135b, upregulated in breast cancer, promotes cell growth and disrupts the cell cycle by regulating LATS2.","authors":"Kaiyao Hua, Jiali Jin, Junyong Zhao, Jialu Song, Hongming Song, Dengfeng Li, Niraj Maskey, Bingkun Zhao, Chenyang Wu, Hui Xu, Lin Fang","doi":"10.3892/ijo.2025.5802","DOIUrl":"10.3892/ijo.2025.5802","url":null,"abstract":"<p><p>Following the publication of the above paper, it was drawn to the Editor's attention by a concerned reader that, for the scratch‑wound assay data shown in Fig. 4A, the '24 h/MCF‑7/mir‑135b inhibitor' data panel looked strikingly similar to the '24 h/MCF‑7/NC' data panel in Fig. 10C, albeit the panels were featured rotated through 180° with respect to each other. The authors were contacted by the Editorial Office to offer an explanation for this possible anomaly in the presentation of the data in this paper, although up to this time, no response from them has been forthcoming. Owing to the fact that the Editorial Office has been made aware of potential issues surrounding the scientific integrity of this paper, we are issuing an Expression of Concern to notify readers of this potential problem while the Editorial Office continues to investigate this matter further. [International Journal of Oncology 48: 1997‑2006, 2016; DOI: 10.3892/ijo.2016.3405].</p>","PeriodicalId":14175,"journal":{"name":"International journal of oncology","volume":"67 6","pages":""},"PeriodicalIF":4.9,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145086234","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"ZBTB20 promotes ferroptosis through inhibiting TMEM109 expression in glioblastoma cells.","authors":"Xuhao Chen, Mingqi Luo, Xiaoyu Niu, Wang Wang, Huanhuan Cao, Liwei Zhang, Ruolun Wei, Ping Duan","doi":"10.3892/ijo.2025.5803","DOIUrl":"https://doi.org/10.3892/ijo.2025.5803","url":null,"abstract":"<p><p>Ferroptosis is an iron‑dependent type of regulated cell death which is dysregulated in several tumors, including glioblastoma (GBM). Zinc finger and BTB domain‑containing protein 20 (<i>ZBTB20</i>), a transcription repressor, is expressed at low levels in GBM and suppresses GBM cell proliferation through the ERK signaling pathway. However, the effect of <i>ZBTB20</i> on ferroptosis has not been explored. The present study aimed to explore the role of ZBTB20 in ferroptosis of glioma cells and its underlying mechanism. The present study demonstrated that both <i>ZBTB20</i> expression and ferroptosis levels in GBM cells were lower than that in normal glial cells. Gain‑ and loss‑of‑function experiments revealed that <i>ZBTB20</i> overexpression promoted ferroptosis and <i>ZBTB20</i> knockdown inhibited ferroptosis in GBM cells. Moreover, the results demonstrated that <i>ZBTB20</i> transcriptionally repressed the expression of transmembrane protein 109 (<i>TMEM109</i>) in GBM cells, assessed using dual‑luciferase reporter and chromatin immunoprecipitation assays. TMEM109 is mainly localized on the endoplasmic reticulum (ER) membrane of cells and regulates calcium leakage at the ER or sarcoplasmic reticulum. The present study revealed that <i>TMEM109</i> overexpression inhibited ferroptosis and <i>TMEM109</i> knockdown promoted ferroptosis in GBM cells. Using co‑transfection experiments, it was further revealed that the promotive effect of <i>ZBTB20</i> can reverse the inhibitory effect of TMEM109 on ferroptosis. In conclusion, the findings indicated that <i>ZBTB20</i> promotes ferroptosis in GBM cells through transcriptionally repressing the expression of <i>TMEM109</i>.</p>","PeriodicalId":14175,"journal":{"name":"International journal of oncology","volume":"67 6","pages":""},"PeriodicalIF":4.9,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145148879","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"[Expression of Concern] Podoplanin‑mediated TGF‑β‑induced epithelial-mesen-chymal transition and its correlation with bHLH transcription factor DEC in TE‑11 cells.","authors":"Yunyan Wu, Qiang Liu, Xu Yan, Yukio Kato, Makiko Tanaka, Sadaki Inokuchi, Tadashi Yoshizawa, Satoko Morohashi, Hiroshi Kijima","doi":"10.3892/ijo.2025.5805","DOIUrl":"https://doi.org/10.3892/ijo.2025.5805","url":null,"abstract":"<p><p>Following the publication of the above paper, it was drawn to the Editor's attention by a concerned reader that, for the scratch‑wound assay experiments shown in Fig. 6 on p. 2318, the 'control siRNA/24 h' and 'podoplanin siRNA/48 h' panels contained an overlapping section of data; such that these data, which were intended to show the results from differently performed experiments, appeared to have been derived from the same original source. Upon analyzing the data independently in the Editorial Office, it came to light that, in addition to control blots, the podoplanin blots were duplicated in Fig. 2A and B, and also in Fig. 3A and B, although it wasn't clear whether this was simply the way in which the authors had chosen to arrange the data in these figures, as the reported experimental conditions were the same in the respective figure parts. The authors were contacted by the Editorial Office to offer an explanation for these possible anomalies in the presentation of the data in this paper, although up to this time, no response from them has been forthcoming. Owing to the fact that the Editorial Office has been made aware of potential issues surrounding the scientific integrity of this paper, we are issuing an Expression of Concern to notify readers of this potential problem while the Editorial Office conitnues to investigate this matter further. [International Journal of Oncology 48: 2310‑2320, 2016; DOI: 10.3892/ijo.2016.3445].</p>","PeriodicalId":14175,"journal":{"name":"International journal of oncology","volume":"67 6","pages":""},"PeriodicalIF":4.9,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145148908","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Role of metabolic reprogramming of cancer‑associated fibroblasts in tumor development and progression (Review).","authors":"Ruyue Li, Yintao Li","doi":"10.3892/ijo.2025.5796","DOIUrl":"10.3892/ijo.2025.5796","url":null,"abstract":"<p><p>The occurrence and development of tumors is affected by tumor cells themselves and various components of the tumor microenvironment (TME). Among these, cancer‑associated fibroblasts (CAFs), the main stromal component, can differentiate from different cell types and play an important role in the TME. The present review summarized the role of the metabolic reprogramming of CAFs in tumor development and progression. As the rapid growth of tumors is a process inseparable from energy supply and the TME is characterized by hypoxia and nutrient deficiencies, metabolic reprogramming can reverse the effects of a lack of energy supply in the TME. Studies have found that CAFs can affect tumor proliferation, migration, invasion, metastasis and drug resistance by changing metabolic patterns. The present review promoted research on the metabolic reprogramming of CAFs and emphasized the importance of considering the heterogeneity and plasticity of CAFs in the TME, which will lead to the development of more effective therapeutic strategies that target specific metabolic pathways in CAFs, potentially improving the efficacy of cancer treatments and overcoming drug resistance.</p>","PeriodicalId":14175,"journal":{"name":"International journal of oncology","volume":"67 5","pages":""},"PeriodicalIF":4.9,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12425346/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144953961","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Progerin regulates actin cytoskeletal remodeling and inhibits EMT and metastasis in triple‑negative breast cancer cells.","authors":"Xinxian Huang, Weizhao Luo, Weixian Liu, Xinguang Liu, Weichun Chen","doi":"10.3892/ijo.2025.5798","DOIUrl":"10.3892/ijo.2025.5798","url":null,"abstract":"<p><p>Triple‑negative breast cancer (TNBC) is a subtype of breast cancer, known for its poor prognosis due to its high invasiveness, strong metastatic tendencies and propensity for recurrence. Epithelial to mesenchymal transition (EMT) is a crucial process in tumor invasion and metastasis and in the formation of cancer‑initiating cells. Hutchinson‑Gilford progeria is a rare condition characterized by accelerated aging, caused by a mutated form of lamin A, known as progerin. The present study aimed to investigate the effect of progerin overexpression on TNBC and uncover its underlying mechanisms of action. Therefore, cell senescence was assessed using senescence‑associated β‑galactosidase staining, while cell proliferation was measured by colony formation, Cell Counting Kit‑8 and EdU assays. Additionally, cell metastasis was evaluated using wound‑healing, Transwell and cell adhesion assays. Immunofluorescence staining was carried out to observe actin cytoskeleton and nuclear morphology. The results showed that progerin markedly suppressed the colony formation, migration, invasion and adhesion abilities of BT‑549 and MDA‑MB‑231 TNBC cell lines, without affecting cell senescence or proliferation. In addition, progerin overexpression altered nuclear morphology and actin cytoskeleton organization in TNBC cells. Furthermore, the expression levels of the mesenchymal markers, N‑cadherin, vimentin, Snail and Slug, were reduced, while those of the epithelial marker, E‑cadherin, were enhanced in TNBC cells. Overall, the results of the present study suggested that progerin overexpression could inhibit TNBC cell metastasis, probably via actin cytoskeleton remodeling and regulate the expression levels of the cytoskeletal‑related proteins, anillin and β‑catenin, and those of the EMT‑related ones. The aforementioned findings could provide novel insights into the identification of potential molecular targets for breast cancer therapy.</p>","PeriodicalId":14175,"journal":{"name":"International journal of oncology","volume":"67 5","pages":""},"PeriodicalIF":4.9,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12456472/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145040082","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Potential of Fibulin2 as a therapeutic target against cancer and as a diagnostic marker (Review).","authors":"Yongqiang Yang, Zi Wang, Lian Weng, Jun Fei, Zhong Li","doi":"10.3892/ijo.2025.5799","DOIUrl":"10.3892/ijo.2025.5799","url":null,"abstract":"<p><p>Cancers are not merely composed of tumor cells; rather, they constitute a complex tumor microenvironment (TME) comprising diverse cell types and noncellular factors. Extracellular matrix (ECM) represents a critical component of the TME. Fibulin2 participates in ECM formation in various tumors, and its altered expression in multiple malignancies can affect tumor cell proliferation and invasiveness. Additionally, Fibulin2 has emerged as a potential biomarker in various cancer types and serves a pivotal role in tumor progression. Consequently, therapeutic strategies targeting Fibulin2 hold considerable promise. However, the research and development of Fibulin2‑targeted therapeutics has progressed at a relatively slow pace. Therefore, the roles and mechanisms of Fibulin2 in various malignancies, along with investigations into its utility as a biomarker, are comprehensively discussed in the present review. This may provide valuable guidance for the clinical translation and application of Fibulin2‑targeted therapies, and the utilization of Fibulin2 as a predictive biomarker.</p>","PeriodicalId":14175,"journal":{"name":"International journal of oncology","volume":"67 5","pages":""},"PeriodicalIF":4.9,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12456471/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145040112","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Harnessing TP73‑targeted nintedanib: A novel strategy to halt triple‑negative breast cancer via p53‑PPARα/PI3K‑Akt pathway suppression.","authors":"Xiaomeng Zou, Shiyu Li, Sisi Huang, Ruilan Niu, Gang Liu, Zhili Wang","doi":"10.3892/ijo.2025.5794","DOIUrl":"10.3892/ijo.2025.5794","url":null,"abstract":"<p><p>Triple‑negative breast cancer (TNBC) is an aggressive malignancy with limited treatment options, leading to poor clinical outcomes and the need for novel therapeutic approaches. Nintedanib, a United States Food and Drug Administration‑approved multi‑kinase inhibitor with anti‑fibrotic and anti‑angiogenic properties, has shown promise in cancer treatment. However, its precise molecular effects on TNBC have not yet been fully elucidated. Therefore, the present study aimed to investigate the therapeutic potential of nintedanib in TNBC using <i>in vitro</i> and <i>in vivo</i> models, specifically focusing on its regulatory effects on key oncogenic pathways. The present study utilized TNBC cell lines (MDA‑MB‑231 and 4T1) and BALB/c mice to evaluate the antitumor efficacy of nintedanib. Cell viability and clonogenic capacity were assessed using Cell Counting Kit‑8 and colony formation assays. Subsequently, apoptosis induction and cell cycle progression were determined by flow cytometry, and cell migration and invasion were analyzed through scratch and Transwell assays. To identify underlying mechanisms, potential molecular targets were identified via bioinformatics and network pharmacology, and were validated through western blotting, immunofluorescence and immunohistochemistry. Finally, an orthotopic TNBC mouse model was established and monitored in real time by multimodal ultrasound imaging. The results revealed that nintedanib significantly inhibited TNBC cell proliferation and suppressed stem cell‑like properties. Furthermore, it induced cell cycle arrest at the G₂/M phase and promoted apoptosis. Mechanistic analysis revealed that nintedanib activated tumor protein p73 (TP73), leading to the disruption of the p53‑peroxisome proliferator‑activated receptor α (PPARα)/PI3K‑Akt signaling axis. Additionally, it downregulated epithelial‑mesenchymal transition (EMT) markers, including Snail and zinc finger E‑box‑binding homeobox protein 1, thereby mitigating tumor invasiveness. <i>In vivo</i>, nintedanib treatment effectively reduced tumor growth, angiogenesis and stiffness, indicating its potential as a viable therapeutic agent for TNBC. In conclusion, nintedanib exerts potent anti‑TNBC effects by modulating TP73, disrupting oncogenic signaling via the p53‑PPARα/PI3K‑Akt axis, and attenuating EMT‑associated transcription factors. These findings highlight its potential as a promising targeted therapy for TNBC, warranting further clinical exploration.</p>","PeriodicalId":14175,"journal":{"name":"International journal of oncology","volume":"67 5","pages":""},"PeriodicalIF":4.9,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12425344/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144953910","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"[Corrigendum] Furin promotes epithelial‑mesenchymal transition in pancreatic cancer cells via Hippo‑YAP pathway.","authors":"Youli Zhang, Meng Zhou, Hong Wei, Hailang Zhou, Junbo He, Ying Lu, Dawei Wang, Baoding Chen, Jian Zeng, Wanxin Peng, Fengyi Du, Aihua Gong, Min Xu","doi":"10.3892/ijo.2025.5797","DOIUrl":"10.3892/ijo.2025.5797","url":null,"abstract":"<p><p>Following the publication of the above article, the authors drew to the Editor's attention that the image in Fig. 3A on p. 1356 for the 'Migration/BxPC3/sh‑EGFP' experiment was mistakenly presented. This error arose as a consequence of a mistake that was made during the preparation of the final images. Furthermore, upon performing an independent analysis of the data in this paper in the Editorial Office, it came to light that, for the colony‑formation assay experiments shown in Fig. 2F on p. 1355, the image selected for the 'PaTu8988/Flag‑Furin' experiment had already appeared in a different context in another paper published by the same authors, also in the journal <i>International Journal of Oncology</i>. After having examined their original data, the authors realize that this second figure in the paper had also been inadvertently assembled incorrectly. The revised versions of Fig. 2 (now showing the data correctly for the for the 'PaTu8988/Flag‑Furin' experiment) and Fig. 3 (showing the correct data for the 'Migration/BxPC3/sh‑EGFP' experiment) are shown on the next two pages. Note that the errors made during the compilation of these figures did not affect the overall results and conclusions reported in the paper. The authors are grateful to the Editor of <i>International Journal of Oncology</i> for granting them the opportunity to publish this corrigendum, and all the authors agree with its publication; furthermore, they apologize to the readership of the journal for any inconvenience caused. [International Journal of Oncology 50: 1352‑1362, 2017; DOI: 10.3892/ijo.2017.3896].</p>","PeriodicalId":14175,"journal":{"name":"International journal of oncology","volume":"67 5","pages":""},"PeriodicalIF":4.9,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12456469/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144953830","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Lp‑PLA2 in the cancer landscape: From molecular mechanisms to therapeutic potential (Review).","authors":"Xiaorong Yang, Yongbo Tu, Na Liang, Lingli Li, Jian Zhang, Jingyu Xu, Chunming Li","doi":"10.3892/ijo.2025.5793","DOIUrl":"10.3892/ijo.2025.5793","url":null,"abstract":"<p><p>Lipoprotein‑associated phospholipase A2 (Lp‑PLA2), an important member of the phospholipase A2 superfamily, was originally investigated for its proinflammatory role in cardiovascular diseases. Recent studies have revealed its significant role in tumorigenesis: It can act as either a tumor promoter or a tumor suppressor depending on the context. The present review systematically outlined the dual mechanisms by which Lp‑PLA2 contributes to cancer pathogenesis. As a tumor promoter, it promotes cancer progression via the induction of epithelial‑mesenchymal transition, glutathione peroxidase 4‑mediated resistance to ferroptosis, and vascular endothelial growth factor‑-dependent angiogenesis; conversely, as a tumor suppressor, it inhibits tumor growth by suppressing the Wnt/β‑catenin pathway in breast cancer gene 1‑mutated cancers or by promoting apoptosis. Mechanistic investigations clarify the interactions between Lp‑PLA2 and critical oncogenic pathways, such as the Notch and HIF1α pathways, while emphasizing the functional dichotomy that is influenced by the microenvironment. Current evidence supports the development of microenvironment‑guided targeting strategies and the potential value of Lp‑PLA2 as a prognostic biomarker and therapeutic target. These findings contribute to a theoretical framework for comprehending the context‑dependent roles of Lp‑PLA2 and may guide the development of innovative therapeutic approaches.</p>","PeriodicalId":14175,"journal":{"name":"International journal of oncology","volume":"67 5","pages":""},"PeriodicalIF":4.9,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12425350/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144953924","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}