Human Cell最新文献

{"title":"Deciphering the immunological landscape of HR + metastatic breast cancer: insights from single-cell transcriptomics.","authors":"Lifang He, Qianqian Zhao, Zexiao Chen, Lijuan He, Zhaochang Qi, Jundong Wu, Kexiang Zhou, Yukun Cui","doi":"10.1007/s13577-026-01384-2","DOIUrl":"https://doi.org/10.1007/s13577-026-01384-2","url":null,"abstract":"<p><p>Breast cancer remains the leading cause of cancer-related mortality among women worldwide, primarily due to metastatic complications. The immune components of the tumor microenvironment (TME) significantly influence metastatic progression. The objective of this study was to uniquely characterize the TME of hormone receptor-positive (HR +) breast cancer with a focus on ovarian metastasis using single-cell RNA sequencing. We delineated the cellular architecture of breast cancer tissues. A total of 9 cell types in 18 clusters were identified, including T cell, B cell and plasma, macrophage, neutrophil, fibroblast, macrophage, endothelial, basal, luminal, SMC (smooth muscle cells) and proliferation cells. Furthermore, macrophages were divided into tumor-associated macrophages and monocyte macrophages, with detailed marker gene analysis. Key statistical findings include the identification of five critical genes (GPR183, BHLHE41, CD83, SLC25A37, and SELL) associated with macrophage functionality. In vivo validation using immunohistochemistry on clinical samples from 10 breast cancer patients with ovarian metastases confirmed that GPR183, BHLHE41, and CD83 were highly expressed in tumor tissues, while SLC25A37 and SELL were highly expressed in adjacent normal tissues. Furthermore, survival analysis correlated the expression levels of these genes with patient outcomes, thus presenting potential prognostic biomarkers. Our study contributes to a deeper insight of the tumor microenvironment in HR + metastatic breast cancer, and offers potential targets for developing novel therapeutic interventions aimed at mitigating metastatic progression and improving clinical outcomes for HR + breast cancer patients.</p>","PeriodicalId":49194,"journal":{"name":"Human Cell","volume":"39 5","pages":""},"PeriodicalIF":3.1,"publicationDate":"2026-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147845107","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Transcriptomic landscape of oral potentially malignant disorders: a meta-analysis approach.","authors":"Vaishnav Vasudevan, Gangotri Siddappa, Reba Elsa Sam, H K Madhumathi, Anela Thomas, Sumsum P Sunny, Vivek Shetty, Vidya Bhushan, Yogesh Dokhe, Vijay Pillai, Praveen Birur, Moni A Kuriakose, Amritha Suresh","doi":"10.1007/s13577-026-01373-5","DOIUrl":"https://doi.org/10.1007/s13577-026-01373-5","url":null,"abstract":"<p><p>Early detection of potentially malignant and malignant lesions in the oral cavity is mandatory for reduction in oral cancer incidence, detection at an early stage and improving survival. The objective of this study was to catalogue the transcriptomic pattern across pre-cancerous stages, identify the major signalling processes, and infiltrating immune cell subtypes using the integrated, multi-dataset, meta-analysis approach. Following a search in the public databases, a total of five datasets were included in the study. The patient samples were stratified to identify the changes in high-grade dysplasia (HGD, moderate/severe dysplasia) as opposed to low-risk lesions (LRL, benign/OPMD) and low-grade dysplasia (LGD). Weighted gene co-expression network analysis (WGCNA; p < 0.05, |Correlation coefficient|:0.3) integrated with differential gene expression (DEG; p < 0.05, Fold change: 1.5) analysis revealed alterations in low-to-high-risk lesions included changes in DNA replication, loss of cell adhesions converging on a hub panel of tumor promoter/suppressors. The shift to high grade dysplasia was marked by enhanced immune/cytokine signalling with hub-gene network driving metabolic regulation, immune evasion, and ECM-stroma interaction. In transformed lesions, the immune-modulatory environment persisted, now accompanied by a notable downregulation of interferon (IFN) signalling. Interferon-inducible network and stemness induction were key hub gene networks. Digital cytometric analysis indicated specific enrichment of T regulatory cells and dendritic cells in differentiating the grades of dysplasia, while T helper cells were specific for malignant transformation. Collectively, these results indicate the role of immune surveillance during oral carcinogenesis. The distinct molecular/immunological shifts during dysplastic progression and malignant transformation represent critical milestones in oral potentially malignant disorder (OPMD) progression, offering actionable insights for prognosis, prevention, and therapeutic intervention.</p>","PeriodicalId":49194,"journal":{"name":"Human Cell","volume":"39 5","pages":""},"PeriodicalIF":3.1,"publicationDate":"2026-05-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147845084","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Heterogeneity of HTLV-1 proviral integration sites and internal structures in the ATL cell line MT-1.","authors":"Misaki Izaki, Yuki Hashikura, Kunihiko Umekita, Kazumi Umeki, Taiga Miyazaki","doi":"10.1007/s13577-026-01385-1","DOIUrl":"https://doi.org/10.1007/s13577-026-01385-1","url":null,"abstract":"<p><p>Human T-cell leukemia virus type 1 (HTLV-1) causes adult T-cell leukemia (ATL). The ATL-derived cell line MT-1 is used to study HTLV-1 biology and leukemogenesis. However, the proviral integration sites and internal structures of HTLV-1 are not comprehensively characterized in MT-1 cells. We analyzed two independently maintained MT-1 cell lines (MT-1 J and MT-1 M) using long PCR, quantitative PCR-based proviral load analysis, inverse long PCR, inverse PCR, integration site-specific PCR, direct sequencing, and Rapid Amplification of Integration Site without Interference by Genomic DNA contamination. Long PCR and proviral load analyses demonstrated that MT-1 cells harbor multiple full-length and defective HTLV-1 proviruses. MT-1 J cells exhibited reduced proviral load in the pX region, suggesting the presence of pX-lacking proviruses. Inverse long PCR and inverse PCR revealed at least five proviral integration sites in MT-1 J cells; MT-1 M cells contained three. Site-specific PCR confirmed the differential preservation of integration sites. Sequence analysis revealed two full-length proviruses and three type I defective proviruses with distinct internal deletions, including an unreported provirus with a large deletion encompassing pX. Rapid Amplification of Integration Site without Interference by Genomic DNA contamination identified major proviral clones shared between MT-1 J and MT-1 M cells, while revealing differences in clone frequencies and minor integration sites. The MT-1 cell line is a polyclonal population containing multiple full-length and defective HTLV-1 proviruses. Its proviral composition can change during long-term in vitro passaging. This heterogeneity should be considered when interpreting results obtained using MT-1 cells in HTLV-1 and ATL research.</p>","PeriodicalId":49194,"journal":{"name":"Human Cell","volume":"39 5","pages":""},"PeriodicalIF":3.1,"publicationDate":"2026-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13132914/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147822849","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Establishment and characterization of a novel HBV-integrated hepatic sarcomatoid carcinoma cell line.","authors":"Jiayin Dai, Fang Cao, Zhenli Yang, Kun Dong, Xiaozheng Huang, Xiaocui Bian, Yuqin Liu","doi":"10.1007/s13577-026-01382-4","DOIUrl":"https://doi.org/10.1007/s13577-026-01382-4","url":null,"abstract":"<p><p>Hepatic sarcomatoid carcinoma (HSC) is a rare and highly aggressive liver malignancy with an extremely poor prognosis. The lack of well-validated cellular models has severely limited mechanistic and translational research on this disease. In this study, we established and comprehensively characterized a novel HSC cell line, designated PUMC-LICA3. This cell line was derived from surgically resected tumor tissue of a 58-year-old male patient and has been continuously cultured for more than 40 passages, with a population doubling time of 51.77 h and an epithelial-like morphology. Long-read sequencing identified HBV DNA integration at chromosome 17p11.2 without detectable covalently closed circular DNA (cccDNA) or viral antigen expression, indicating a non-replicative viral status. PUMC-LICA3 exhibited 100% tumorigenicity in NOD/SCID mice. Xenograft tumors displayed immunohistochemical features consistent with sarcomatoid carcinoma, characterized by the co-expression of epithelial markers (CK and CK19) and the mesenchymal marker vimentin. E-cadherin expression was patchy, with partial loss in subsets of tumor cells, whereas N-cadherin was diffusely expressed. Notably, PUMC-LICA3 exhibited a high epithelial-mesenchymal transition (EMT) score and, among 22 hepatocellular carcinoma (HCC), clustered most closely with JHH-6 and SNU-387. Drug sensitivity assays showed that the cell line was sensitive to cisplatin, doxorubicin and sorafenib, but resistant to 5‑fluorouracil. Whole-exome sequencing (WES) analysis revealed that the cell line largely preserved the genetic characteristics of its parental tumor throughout long-term culture. In conclusion, the newly established PUMC-LICA3 cell line represents a reliable and valuable experimental model for investigating the biological characteristics and therapeutic strategies of hepatic sarcomatoid carcinoma.</p>","PeriodicalId":49194,"journal":{"name":"Human Cell","volume":"39 5","pages":""},"PeriodicalIF":3.1,"publicationDate":"2026-04-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147786916","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Culture-dependent baseline states and drug response programs in myxofibrosarcoma models across 2D and 3D systems.","authors":"Yuki Yoshimatsu, Yomogi Shiota, Tadashi Kondo","doi":"10.1007/s13577-026-01372-6","DOIUrl":"https://doi.org/10.1007/s13577-026-01372-6","url":null,"abstract":"<p><p>Myxofibrosarcoma (MFS) is a rare soft-tissue sarcoma with limited systemic therapy options, necessitating preclinical platforms that better simulate clinical drug responses. We investigated how 2D monolayers versus 3D spheroids shape the baseline transcriptome and doxorubicin (DOX)-responsive programs across six patient-derived MFS cell lines. RNA sequencing revealed that 3D culture induces a distinct transcriptomic state characterized by the enrichment of microenvironment-associated stress programs, such as hypoxia, inflammatory/NF-κB signaling, and glycolysis, alongside the suppression of proliferation-related pathways. Although the global DOX-induced transcriptional response was highly environment-dependent, we identified a robust core of six regulators-MCRIP1, FGF12, HGF, EMSY, FZD2, and SECISBP2-whose transcriptional changes consistently correlated with cell survival rates across both 2D and 3D geometries. These genes are involved in transcriptional plasticity, redox homeostasis, and bypass survival signaling, providing a mechanistic basis for DOX resistance that transcends culture conditions. Our findings demonstrate that while culture geometry is a critical determinant of the MFS transcriptome, a robust set of environment-agnostic regulators dictates DOX efficacy. Integrating 3D systems with these specific transcriptomic readouts enhances the interpretability of drug screenings and supports the prioritization of rational therapeutic combinations for this rare sarcoma.</p>","PeriodicalId":49194,"journal":{"name":"Human Cell","volume":"39 5","pages":""},"PeriodicalIF":3.1,"publicationDate":"2026-04-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147786860","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Generation of a human-induced pluripotent stem cell line from a retinitis pigmentosa patient carrying biallelic mutations in EYS gene.","authors":"Jueun Kim, Juyeong Yu, Donghyun Kim, Borami Shin, Johnny Kim, Yong Soo Park, Kee-Pyo Kim","doi":"10.1007/s13577-026-01383-3","DOIUrl":"https://doi.org/10.1007/s13577-026-01383-3","url":null,"abstract":"<p><p>Retinitis pigmentosa (RP) is a hereditary retinal disorder characterized by progressive degeneration of photoreceptor cells in the retina, leading to gradual vision loss. Symptoms of RP typically begin with night blindness and progressive loss of peripheral vision, eventually leading to severe tunnel vision and, in advanced stages, loss of central vision or complete blindness. To date, no effective therapeutic strategies have been developed to halt disease progression, mitigate vision loss, or achieve a complete cure, and currently available disease models have limitations in fully recapitulating the human disease phenotype. In this study, we generated a human induced pluripotent stem cell (hiPSC) line, CUKi001-A, from fibroblasts of a 20-year-old male patient with EYS-associated RP using lentiviral delivery of reprogramming factors OCT4, SOX2, KLF4, and c-MYC. The CUKi001-A iPSC line carried heterozygous missense mutations in exon 16 (c.2528G > A, p.G843E) and exon 37 (c.7382 T > C, p.L2461S) of the EYS gene, consistent with its parental fibroblasts. The established iPSC line exhibited typical iPSC morphology, a normal karyotype, expression of key pluripotency markers, and the ability to differentiate into derivatives of all three germ layers. The hiPSC line established in this study provides a valuable platform for investigating the pathogenic mechanisms of EYS-associated RP and for developing potential therapeutic strategies.</p>","PeriodicalId":49194,"journal":{"name":"Human Cell","volume":"39 5","pages":""},"PeriodicalIF":3.1,"publicationDate":"2026-04-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147724631","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pathogenesis and therapeutic strategies for neuropsychiatric lupus centered on innate immune activation.","authors":"Wataru Nagata, Toshiaki Ishizuka","doi":"10.1007/s13577-026-01381-5","DOIUrl":"10.1007/s13577-026-01381-5","url":null,"abstract":"<p><p>Neuropsychiatric systemic lupus erythematosus (NPSLE) is a serious central nervous system complication of systemic lupus erythematosus (SLE) that markedly reduces patient quality of life. Despite its clinical importance, the underlying mechanisms remain incompletely defined, and effective treatments are limited. In this review, we synthesize preclinical and clinical evidence that aberrant activation of innate immunity by self-nucleic acids and consequent overproduction of Type I interferons (IFN-I) constitute a central pathogenic axis in NPSLE. IFN-I and other inflammatory mediators promote disruption of the blood-brain barrier (BBB), enabling entry of autoantibodies, cytokines, and immune cells into the brain. These factors, together with damage-associated molecular patterns, activate microglia and astrocytes, driving sustained neuroinflammation that provokes synaptic loss, neurotransmitter dysregulation, excitotoxic neuronal injury, impaired neurogenesis, and mitochondrial dysfunction-mechanisms that underlie cognitive impairment, mood disorders, and other neuropsychiatric manifestations. We review therapeutic strategies targeting each step of this cascade, including blockade of IFN-I signaling (e.g., anifrolumab), inhibition of endosomal nucleic acid sensing (TLR antagonists), cytokine and JAK inhibition, modulation of microglial function (CSF1R inhibitors), and approaches to protect or restore BBB integrity (e.g., statins). Finally, we discuss biomarker-guided patient stratification and trial designs necessary to address NPSLE heterogeneity and accelerate the development of personalized therapies. By elucidating the cellular responses of the neurovascular unit to innate immune insults, this review provides a molecular framework for developing targeted therapies for NPSLE.</p>","PeriodicalId":49194,"journal":{"name":"Human Cell","volume":"39 5","pages":""},"PeriodicalIF":3.1,"publicationDate":"2026-04-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13086751/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147700339","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Human peritoneal CCR2^LowCRIg^High macrophage subset exhibits embryonic origin-like phenotypes.","authors":"Naofumi Takahashi, Sara A Habash, Yoshihiro Komohara, Shingo Usuki, Kei-Ichiro Yasunaga, Shinjiro Hino, Randa A Abdelnaser, Thorbjorg Einarsdottir, Takushi Nomura, Atsuko Yonemura, Takatsugu Ishimoto, Shinya Suzu","doi":"10.1007/s13577-026-01379-z","DOIUrl":"https://doi.org/10.1007/s13577-026-01379-z","url":null,"abstract":"<p><p>Recent studies in mouse models have demonstrated that macrophages in adult tissues are maintained not only by the differentiation of bone marrow-derived monocytes but also by the proliferation of macrophages originating from the yolk sac or fetal liver. However, the extent to which this paradigm shift occurs in human tissues is not fully understood. In this study, we detected a human peritoneal macrophage subset that exhibited embryonic origin-like phenotypes. Macrophages in the ascites of patients with gastric cancer were divided into CCR2^Low and CCR2^High subsets, the ratios of which varied among donors. The gene expression profiles of these subsets were similar to those of the macrophage subsets in the heart. CRIg was recently reported as a marker for distinguishing between two macrophage subsets in the ascites of patients with cirrhosis. CCR2^Low and CCR2^High subsets expressed high and low levels of CRIg, respectively. Importantly, the CCR2^LowCRIg^High subset expressed the cell proliferation marker Ki67 and the recently proposed core markers (TIMD4, LYVE1, and FOLR2) of embryo-derived macrophages at higher levels than the CCR2^HighCRIg^Low subset. Moreover, many other markers shared by TIMD4⁺LYVE1⁺FOLR2⁺ macrophages in heart, lung, kidney, and liver exhibited similar expression patterns in the peritoneal CCR2^LowCRIg^High subset. These results suggest that the CCR2^LowCRIg^High subset in the peritoneal cavity contains macrophages with embryonic origin.</p>","PeriodicalId":49194,"journal":{"name":"Human Cell","volume":"39 5","pages":""},"PeriodicalIF":3.1,"publicationDate":"2026-04-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147700361","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Extracellular vesicle-derived CDCP1 promotes chemoresistance and macrophage polarization in breast cancer.","authors":"Yibing Liu, Li Ma, Ting Zhu, Di Wu, Yonglei Liu","doi":"10.1007/s13577-026-01371-7","DOIUrl":"https://doi.org/10.1007/s13577-026-01371-7","url":null,"abstract":"<p><p>Breast cancer derived extracellular vesicles (EVs) mediate tumor progression through surface protein-dependent intercellular communication; however, their molecular heterogeneity remains poorly characterized. In this study, we employed a proximity-dependent barcoding assay (PBA) together with patient-derived organoid (PDO) models and identified CDCP1 as a key driver of EV-mediated oncogenesis. PBA-based surface proteomics revealed CDCP1 as the most upregulated protein in breast cancer-derived EVs compared with EVs from normal tissues. Clinical validation confirmed elevated CDCP1 expression in tumor tissues and matched EVs. PDOs generated from fresh clinical specimens recapitulated CDCP1 expression levels of the parental tumors and secreted CDCP1-enriched EVs. Functional experiments showed that CDCP1-knockdown EVs suppressed PDO proliferation and sensitized tumors to chemotherapy. Mechanistically, CDCP1-positive EVs promoted macrophage polarization toward an M2 phenotype, accompanied by upregulation of IL-10 and TGF-β and CCL22. Multiplex immunofluorescence confirmed that CDCP1-high tumors exhibited increased co-localization of CD68⁺ and CD163⁺ macrophages. These results establish CDCP1 as a master regulator of EV driven breast cancer progression, linking surface proteome remodeling to chemo-resistance and immunosuppressive microenvironment reprogramming. The integration of single-EV profiling and PDO modeling establishes a translational framework for targeting CDCP1 as a promising therapeutic target and a candidate biomarker for future liquid biopsy development in aggressive breast cancer subtypes.</p>","PeriodicalId":49194,"journal":{"name":"Human Cell","volume":"39 4","pages":""},"PeriodicalIF":3.1,"publicationDate":"2026-04-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147678072","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Ethanol-induced NINJ1 oligomerization might contribute to the lytic death of granulosa cells in PCOS.","authors":"Caglar Berkel","doi":"10.1007/s13577-026-01378-0","DOIUrl":"https://doi.org/10.1007/s13577-026-01378-0","url":null,"abstract":"","PeriodicalId":49194,"journal":{"name":"Human Cell","volume":"39 4","pages":""},"PeriodicalIF":3.1,"publicationDate":"2026-04-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147678090","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}