Molecular Cancer最新文献

{"title":"Correction: Cell‑autonomous IL6ST activation suppresses prostate cancer development via STAT3/ARF/p53‑driven senescence and confers an immune‑active tumor microenvironment.","authors":"Christina Sternberg, Martin Raigel, Tanja Limberger, Karolína Trachtová, Michaela Schlederer, Desiree Lindner, Petra Kodajova, Jiaye Yang, Roman Ziegler, Jessica Kalla, Stefan Stoiber, Saptaswa Dey, Daniela Zwolanek, Heidi A Neubauer, Monika Oberhuber, Torben Redmer, Václav Hejret, Boris Tichy, Martina Tomberger, Nora S Harbusch, Jan Pencik, Simone Tangermann, Richard Moriggl, Vojtech Bystry, Jenny L Persson, Gerda Egger, Sarka Pospisilova, Robert Eferl, Peter Wolf, Felix Sternberg, Sandra Högler, Sabine Lagger, Stefan Rose-John, Lukas Kenner","doi":"10.1186/s12943-026-02665-y","DOIUrl":"10.1186/s12943-026-02665-y","url":null,"abstract":"","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"25 1","pages":""},"PeriodicalIF":42.2,"publicationDate":"2026-07-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13334746/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148397177","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":"Breaking the immune \"cold niche\" in bone metastasis: core mechanisms of the multidimensional interwoven regulatory network and precision breakthrough strategies.","authors":"Yun Mao,Feiyu Xie,Xuelei Chu,Wanhui Zhang,Ke Dou,Beier Hu,Ling Fu,Zhixun Ding,Shijie Zhu,Wen Cao,Yongjie He","doi":"10.1186/s12943-026-02731-5","DOIUrl":"https://doi.org/10.1186/s12943-026-02731-5","url":null,"abstract":"Bone metastasis is a pivotal hallmark of advanced malignant tumors. It severely impairs the therapeutic efficacy of immune checkpoint inhibitors (ICIs) and serves as an independent risk factor for poor prognosis of immunotherapy in solid tumors. Most existing reviews are confined to traditional research frameworks and have not yet resolved this clinical dilemma. This paper systematically elaborates on the core mechanisms underlying the poor efficacy of immunotherapy for bone metastasis. It clarifies that the immune suppression mediated by the bone metastatic microenvironment (BME) is not induced by a single factor, but rather a consequence of the cross-regulation of immunity, metabolism, bone matrix, blood vessels, epigenetics, microbiota, and nerves. From seven dimensions-immune cell-mediated immune escape, bone matrix-immune cell crosstalk, vascular-mediated immune suppression, metabolic-immune cross-regulation, epigenetic disorders, microbiota-osteoimmune axis imbalance, and neuro-immune-bone metastasis regulation-the study comprehensively sorts out the key nodes of immunotherapy resistance and clarifies the core cellular, molecular, and microenvironmental interaction mechanisms of this cross-regulatory network. On this basis, this paper explores a multi-target combined therapeutic strategy of \"breaking the vicious cycle by targeting key nodes, restoring anti-tumor immunity with ICIs, and realizing local-systemic synergism\", including combined bone matrix-immune targeted therapy, immune phenotype-based precise treatment, local-systemic synergistic immunotherapy and multi-dimensional microenvironment remodeling regimens.Finally, the paper prospects future research directions, including in-depth mechanism analysis, new target development, precision diagnosis and treatment innovation, and clinical translation. It aims to systematically summarize current mechanisms and provide theoretical reference and novel insights for developing precise immunotherapeutic strategies against bone metastasis.","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"35 1","pages":""},"PeriodicalIF":37.3,"publicationDate":"2026-07-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148380000","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":"Liposomal drug delivery for lung cancer therapy: progress, challenges, and future perspectives.","authors":"Abulfazl Vatankhah,Sepehr Hoseinzadeh Moghaddam,Mohsen Rahmanian,Sarah Khosropanah,Fatemeh Oroojalian,Prashant Kesharwani,Amirhossein Sahebkar","doi":"10.1186/s12943-026-02728-0","DOIUrl":"https://doi.org/10.1186/s12943-026-02728-0","url":null,"abstract":"Liposomes, as one of the most established nanocarriers, have been widely employed in lung cancer therapy, which remains the leading cause of cancer-related mortality worldwide. However, the current landscape of liposomal formulations and the principles guiding their rational design remain insufficiently defined. This review provides a comprehensive analysis of how liposomal delivery systems have been engineered to address biological and therapeutic challenges in lung cancer. We analyze liposome-based delivery of chemotherapeutic agents, including formulations that have advanced to clinical trials, with particular emphasis on strategies developed to overcome multidrug resistance (MDR). Surface engineering and functionalization strategies that enable active targeting and enhance therapeutic efficacy are also reviewed. Liposomal platforms for immunotherapy are examined, alongside their application in delivering phytochemicals, nucleic acid therapeutics, and photo-enabled modalities, including photothermal and photodynamic therapies, which are discussed in dedicated sections. Cutting-edge innovations, such as biomimetic liposomes, stimuli-responsive smart systems, and theranostic designs integrating diagnostic and therapeutic functions, are highlighted. Finally, pulmonary delivery of anticancer agents is evaluated, focusing on formulation parameters informed by current liposome-based evidence and broader lessons from nanomedicine. By providing mechanistic insights, design principles, and translational perspectives, this review offers a unified framework for liposome-based platforms in lung cancer therapy.","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"14 1","pages":""},"PeriodicalIF":37.3,"publicationDate":"2026-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148379849","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":"Correction: Bmi-1 promotes invasion and metastasis, and its elevated expression is correlated with an advanced stage of breast cancer.","authors":"Bao-Hong Guo, Yan Feng, Rong Zhang, Li-Hua Xu, Man-Zhi Li, Hsiang-Fu Kung, Li-Bing Song, Mu-Sheng Zeng","doi":"10.1186/s12943-026-02709-3","DOIUrl":"10.1186/s12943-026-02709-3","url":null,"abstract":"","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"25 1","pages":""},"PeriodicalIF":42.2,"publicationDate":"2026-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13330436/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148376501","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":"Correction: circNFIB1 inhibits lymphangiogenesis and lymphatic metastasis via the miR-486-5p/PIK3R1/VEGF-C axis in pancreatic cancer.","authors":"Yao Kong, Yuting Li, Yuming Luo, Jiang Zhu, Hanhao Zheng, Bowen Gao, Xiaofeng Guo, Zhihua Li, Rufu Chen, Changhao Chen","doi":"10.1186/s12943-026-02730-6","DOIUrl":"10.1186/s12943-026-02730-6","url":null,"abstract":"","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"25 1","pages":""},"PeriodicalIF":42.2,"publicationDate":"2026-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13330144/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148382615","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":"Reprogramming the pancreatic ductal adenocarcinoma microenvironment: a novel integrin-targeted cytotoxin, ProAgio, potentiates chemotherapy.","authors":"Ganji Purnachandra Nagaraju,Sujith Sarvesh,Ravi Chakra Turaga,Dhana Sekhar Reddy Bandi,Ganesh Satyanarayana,Falguni Mishra,Malvika Sharma,Mehmet Akce,Zhi-Ren Liu,Bassel F El-Rayes","doi":"10.1186/s12943-026-02725-3","DOIUrl":"https://doi.org/10.1186/s12943-026-02725-3","url":null,"abstract":"BACKGROUNDPancreatic ductal adenocarcinoma (PDAC) growth and metastasis are influenced by the tumor microenvironment (TME), which includes immune cells, endothelial cells, macrophages, and cancer-associated fibroblasts (CAFs). Since the novel integrin-targeted cytotoxin ProAgio can inhibit activated CAFs and endothelial cells, we investigated its combination with standard of care chemotherapies in genetically engineered mouse (GEM) and orthotopic murine models of PDAC.METHODSWe established metastatic murine KPC-Ganji & Bassel-Luc (mKPC-GB-Luc) cell lines and validated them using bulk RNA sequencing. Two in vivo orthotopic mouse model were used to evaluate ProAgio with chemotherapy. mKPC-GB-Luc was used to evaluate the 5FU, oxaliplatin, and irinotecan (FOI combination), and KPC-ML1-Luc was used to evaluate the gemcitabine, nab-paclitaxel (GPTx combination). Immunohistochemistry was used to measure integrin β3, E-cadherin, and HIF-1α. Hypoxia was evaluated using pimonidazole. Stem cells, CAFs, and immune cell subtypes were quantified by flow cytometry. We evaluated the combination of ProAgio plus gemcitabine in a KPC genetically engineered mouse model (KPC GEM). Two sets of KPC GEM were developed. The first set was used for a survival study. The second set was terminated early and tumors were used for single-cell RNA seq and sequential multiplex immunofluorescence (COMET).RESULTSCompared with the chemo regimen (GPTx or FOI), ProAgio, or sham, the combination of ProAgio plus chemo significantly modulated the TME, reduced tumor weight, reduced hypoxia, and eliminated metastasis to the lungs and liver. The combination of ProAgio and gemcitabine increased overall survival in KPC GEM mice compared with either treatment alone. Single-cell RNA sequencing, flow cytometry, immunofluorescence, immunohistochemistry, and COMET analyses demonstrated that ProAgio plus chemotherapy reprogrammed the PDAC-TME by changing activated CAFs toward a qCAFs (quiescent CAFs), macrophages from protumor to proinflammatory polarization, and activating natural killer (NK) cells, CD4⁺, and CD8⁺ T cells. Combination therapy inhibited PDAC stemness. ProAgio-treated CAFs in vitro exhibited reduced secretion of glycine and cysteine, vital metabolites that support stemness and tumor progression.CONCLUSIONSThese results confirm the novel mechanism of action of ProAgio, which includes reducing hypoxia and modulating TME. The current data provide evidence for potentiation of chemotherapy efficacy by ProAgio.","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"63 1","pages":""},"PeriodicalIF":37.3,"publicationDate":"2026-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148379850","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":"Correction: YTHDF2 in peritumoral hepatocytes mediates chemotherapy-induced antitumor immune responses through CX3CL1-mediated CD8⁺ T cell recruitment.","authors":"Zhenyun Yang, Xin Wang, Yizhen Fu, Weijie Wu, Zili Hu, Qingyang Lin, Wei Peng, Yangxun Pan, Juncheng Wang, Jinbin Chen, Dandan Hu, Zhongguo Zhou, Li Xu, Yaojun Zhang, Jiajie Hou, Minshan Chen","doi":"10.1186/s12943-026-02700-y","DOIUrl":"10.1186/s12943-026-02700-y","url":null,"abstract":"","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"25 1","pages":""},"PeriodicalIF":42.2,"publicationDate":"2026-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13330359/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148382634","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":"IL-17-driven tumor cell-intrinsic inflammatory programming creates an immunotherapy-permissive microenvironment.","authors":"Kosuke Murakami, Shiki Takamura, Chiho Miyagawa, Shiro Takamatsu, Yoko Kashima, Koji Nagaoka, Yukari Kobayashi, Yoshiyuki Hakata, Shigeki Kato, Sachiyo Tsuji-Kawahara, Ding Nan, Ronald Chandler, Satoru Takahashi, Masaaki Miyazawa, Kazuhiro Kakimi, Noriomi Matsumura","doi":"10.1186/s12943-026-02726-2","DOIUrl":"10.1186/s12943-026-02726-2","url":null,"abstract":"<p><strong>Background: </strong>While immune checkpoint inhibitors (ICIs) have failed to improve outcomes in unselected ovarian cancer populations, objective responses are observed in a minority of ovarian clear cell carcinoma (OCCC) cases, implying biological heterogeneity and a yet-undefined immunologically responsive subset within this histotype.</p><p><strong>Methods: </strong>We performed immunohistochemical profiling of tumor-infiltrating immune cells and analyzed transcriptomic data from human OCCC cohorts. Functional studies were conducted using an immunocompetent syngeneic OCCC mouse model to assess the effects of IL-17 on tumor cell inflammatory signaling, immune microenvironment remodeling, and responsiveness to immune checkpoint blockade, including single-cell RNA sequencing of tumor-infiltrating T cells.</p><p><strong>Results: </strong>OCCC exhibited an immune-sparse tumor microenvironment with relative enrichment of CD4⁺ T cells. RORC expression was elevated in OCCC but showed intertumoral heterogeneity. In the transcriptome data (n = 180), an IL17A^high subset (5%), enriched within the RORC^high fraction, exhibited a T cell-inflamed gene expression profile independent of microsatellite instability and tumor mutational burden, yet was not associated with survival. Mechanistically, IL-17 directly activated NF-κB-dependent inflammatory programs in OCCC tumor cells, inducing cytokines and chemokines involved in T-cell recruitment and activation. In the syngeneic model, IL-17 exposure increased intratumoral CD4⁺ and CD8⁺ T-cell infiltration and activation. Single-cell profiling further revealed expansion of Th17/Tfh-like CD4⁺ T cells and cytotoxic, non-terminally exhausted CD8⁺ T cells. Consistent with these changes, anti-PD-L1 therapy improved survival in Th17-biased partial chimera mice.</p><p><strong>Conclusions: </strong>IL-17-responsive, tumor cell-intrinsic inflammatory programming remodels the tumor immune microenvironment toward an immunotherapy-permissive state. These findings establish IL-17-responsive tumor cell inflammatory programming as a mechanistic axis shaping immune checkpoint sensitivity and provide a rationale for biomarker-guided immunotherapy strategies.</p>","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":" ","pages":""},"PeriodicalIF":42.2,"publicationDate":"2026-06-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13348758/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148361660","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":"Dissecting oral premalignant carcinogenesis: spatial omics mechanisms and nanomedicine-driven therapeutic innovation.","authors":"Xinjia Cai,Yingying Cui,Chuanyang Ding,Yan Liu,Tiejun Li","doi":"10.1186/s12943-026-02727-1","DOIUrl":"https://doi.org/10.1186/s12943-026-02727-1","url":null,"abstract":"Oral potentially malignant disorder (OPMD) remains a critical clinical challenge for cancer interception. However, the progression of OPMD toward oral squamous cell carcinoma (OSCC) is driven by profound cellular heterogeneity and dynamic microenvironmental remodeling. The mechanisms underlying these processes are not yet fully understood. Recent advancements in single-cell and spatial omics have facilitated high-resolution decoding of the precancerous landscape, unveiling multistep epithelial cell plasticity, fibroblast heterogeneity with extracellular matrix remodeling, immune suppression, and inflammatory reprogramming, as well as coupled metabolic and redox alterations that govern malignant transformation. These insights into the cellular mechanisms have led to a paradigm shift in the understanding of OPMD, reclassifying it as an ecosystem-level disease rather than a purely epithelial pathology. Nanomedicine is a potent platform for translating mechanistic knowledge into precision diagnostics and interventions at the precancerous stage. Nanomaterial-based strategies have been demonstrated to facilitate several critical processes, including enabling early lesion visualization and risk stratification, immune microenvironment reactivation, anti-fibrotic and anti-inflammatory remodeling, and targeted regulation of metabolic and oxidative stress pathways. A mounting body of evidence from preclinical and clinical studies lends support to the notion that nanotechnology-assisted early detection, microenvironmental reprogramming, and the interception of malignant transformation across oral and other precancerous conditions are indeed feasible. This review integrates single-cell-resolved mechanisms of OPMD progression with state-of-the-art nanomedicine-based diagnostic and therapeutic strategies, highlighting convergent biological axes and translational opportunities. By integrating single-cell biology with nanotechnology-driven precision medicine, this work is expected to improve the development of a nanomedicine framework for early cancer detection and treatment and outline future directions and challenges toward clinical implementation.","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"24 1","pages":""},"PeriodicalIF":37.3,"publicationDate":"2026-06-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148349046","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 plasma proteomic signature of cancer-related sarcopenia implicates the IGFBP axis in muscle dysfunction.","authors":"Filippo Gustavo Dall'Olio,Wael Salem Zrafi,Xinran Song,Littisha Lawrance,Ekaterina Shalimanova,Anna Schwager,Nadia Myszka,Fei Chen,Rebecca Ibrahim,Marie Guinhut,Pierre Busson,Catherine Brenner,Karim Benihoud,Fabrice Barlesi,Caroline Even,Dimitria Brempou,Nathalie Lassau,Claudio Nicotra,Maud Ngo Camus,Marine Aglave,Yohann Loriot,Diana Cardenas,Mariam Jamal-Hanjani,Carla M Prado,Antoine Italiano,Yegor Vassetzky,Benjamin Besse","doi":"10.1186/s12943-026-02716-4","DOIUrl":"https://doi.org/10.1186/s12943-026-02716-4","url":null,"abstract":"BACKGROUNDCancer-related sarcopenia is associated with poor clinical outcomes but remains difficult to define and quantify in routine oncology practice. Current assessments rely on imaging and functional scales that are time-consuming and provide limited biological insight. We aimed to identify a plasma proteomic signature of cancer-related sarcopenia and to uncover circulating mediators involved in its pathophysiology.METHODSPatients were included from two cohorts of the MATCH-R study (NCT02517892): a discovery cohort of advanced cancer patients treated with immunotherapy and an independent validation cohort of metastatic castration-resistant prostate cancer (mCRPC) patients treated with androgen-receptor pathway inhibitors. External validation was performed in the TRACERx cohort of non-small cell lung cancer. Skeletal muscle index at third lumbar vertebra (L3) was quantified using imaging, and ECOG performance status served as a functional proxy. Plasma proteomics was performed using the Olink Explore platform. An extreme gradient boosting (XGBoost) model was trained on a high-contrast subset using a neuromuscular-focused protein panel and validated across cohorts. Functional effects of candidate mediators were assessed in differentiating human myoblasts.RESULTSThe model generated a continuous sarcopenia probability (SP) score that correlated with muscle mass and functional status and consistently stratified overall survival across cohorts. A reduced four-protein model retained comparable performance, supporting translational applicability. Proteins associated with SP included insulin-like growth factor binding protein 1 and 2 (IGFBP1, IGFBP2), and interleukin-6 (IL6). IGFBP1 and IGFBP2 impaired myoblast differentiation, while IL6 induced IGFBP1 expression in liver cells.CONCLUSIONSPlasma proteomics enables scalable and biologically informed assessment of cancer-related sarcopenia, identifies tumor-host mediators of muscle dysfunction, and supports objective patient stratification for therapeutic intervention.","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"34 1","pages":""},"PeriodicalIF":37.3,"publicationDate":"2026-06-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148348996","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}