Platelets最新文献

{"title":"Transcriptomic and functional characterization of megakaryocytic-derived platelet-like particles: impaired aggregation and prominent anti-tumor effects.","authors":"Kaitlin Garofano, Vera Mariani, Kameron Rashid, Sumanun Suwunnakorn, Alfateh Sidahmed, Anelia Horvath, Sanjay B Maggirwar, Travis J O'Brien, Minoli A Perera, Michael Whalen, Norman H Lee","doi":"10.1080/09537104.2024.2449344","DOIUrl":"10.1080/09537104.2024.2449344","url":null,"abstract":"<p><p>Platelet-like particles (PLPs), derived from megakaryocytic cell lines MEG-01 and K-562, are widely used as a surrogate to study platelet formation and function. We demonstrate by RNA-Seq that PLPs are transcriptionally distinct from platelets. Expression of key genes in signaling pathways promoting platelet activation/aggregation, such as the PI3K/AKT, protein kinase A, phospholipase C, and α-adrenergic and GP6 receptor pathways, was missing or under-expressed in PLPs. Functionally, PLPs do not aggregate following epinephrine, collagen, or ADP stimulation. While PLPs aggregated in response to thrombin, they did not display enhanced expression of surface markers P-selectin and activated α_2bβ₃, in contrast to platelets. We have previously demonstrated that platelets physically couple to MDA-PCa-2b and RC77T/E prostate cancer (PCa) cells via specific ligand-receptor interactions, leading to platelet-stimulated cell invasiveness and apoptotic resistance, and reciprocal cell-induced platelet aggregation. In contrast, PLP interactions with PCa cells inhibited both cell invasion and apoptotic resistance while failing to promote PLP aggregation. Moreover, PLPs reduced platelet-PCa cell interactions and antagonized platelet-stimulated oncogenic effects in PCa cells. RNA-Seq analysis identified candidate ligand-transmembrane protein combinations involved in anti-tumorigenic signaling of PLPs to PCa cells. Antibody neutralization of the TIMP3-MMP15 and VEGFB-FGFR1 signaling axes reversed PLP-mediated anti-invasion and apoptotic sensitization, respectively. In summary, PLPs lack many transcriptomic, molecular and functional features of platelets and possess novel anti-tumorigenic properties. These findings indicate that PLPs may have a potential therapeutic role in targeting and disrupting the oncogenic signaling between platelets and cancer cells, offering a new avenue for anti-cancer strategies.</p>","PeriodicalId":20268,"journal":{"name":"Platelets","volume":"36 1","pages":"2449344"},"PeriodicalIF":2.5,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11890189/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142984432","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":"Platelet parameters for distinguishing between inherited macrothrombocytopenia and acquired thrombocytopenia: a retrospective case-control study.","authors":"Wenlan Chen, Yajie Ding, Li Cai, Mei Xue, Abdul Rehman Arif, Heng Mei, Yadan Wang","doi":"10.1080/09537104.2025.2489025","DOIUrl":"https://doi.org/10.1080/09537104.2025.2489025","url":null,"abstract":"<p><p>Inherited macrothrombocytopenia (IMT) is characterized by increased platelet volume. Using platelet parameters, including platelet count, mean platelet volume (MPV), platelet-large cell ratio (P-LCR), and platelet distribution width, to differentiate IMT from acquired thrombocytopenia (AT) in the Chinese population is unclear. This study aimed to evaluate these parameters and determine optimal thresholds for early IMT identification. This single-center, retrospective case-control study included IMT patients from 1 January 2022 to 31 January 2024. Age- and sex-matched AT patients and healthy individuals were selected (1:3 ratio). Platelet parameters were compared using a one-way analysis of variance and the Kruskal-Wallis test. The ability of platelet parameters to identify IMT was assessed using the receiver operating characteristic curve, with the optimal threshold determined using the Youden index. This study included 13 IMT patients, 39 AT patients, and 39 controls. The MPV and P-LCR were significantly higher in IMT than in AT patients (<i>P</i> < 0.05) and strongly differentiated between groups. The area under the curve (95% confidence interval) for MPV and P-LCR were 0.865 (0.724-1.000) and 0.860 (0.719-1.000), respectively. The optimal MPV and P-LCR thresholds for IMT were 14.55 fL and 58%, respectively. The MPV was most important for distinguishing IMT from patients with thrombocytopenia.</p>","PeriodicalId":20268,"journal":{"name":"Platelets","volume":"36 1","pages":"2489025"},"PeriodicalIF":2.5,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144041596","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":"Regulation of lipid metabolism: a new strategy for platelet storage.","authors":"Jieyun Shi, Wenting Wang, Jinmei Xu, Wen Yin","doi":"10.1080/09537104.2025.2465321","DOIUrl":"10.1080/09537104.2025.2465321","url":null,"abstract":"<p><p>Transfusions of platelets are often used as prophylaxis in patients with hematologic malignancies and as treatment for active bleeding. However, platelets are in short supply due to the fact that they could only be kept for 5-7 days in vitro and they lose some of their functionality as a result of platelet storage lesions. To address this issue, refrigeration, cryopreservation and platelet additive solutions have been researched to determine their abilities to extend platelet storage duration. However, refrigerated platelets are quickly cleared after transfusion, while platelets in platelet additive solutions still present issues such as platelets quality and the risk of allergic reactions. Recent studies showed that changes in lipid metabolites during platelet storage and inadequate of fatty acid metabolism may also limit platelet shelf life and function. In this review, we address the principles of lipid metabolism during platelet storage and discuss the strategies for effective platelet storage systems. The findings of this review highlight the role of lipid metabolism during platelet storage, providing insights into future research focused on extending the preservation period and function of platelet.</p>","PeriodicalId":20268,"journal":{"name":"Platelets","volume":"36 1","pages":"2465321"},"PeriodicalIF":2.5,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143414952","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":"Effect of aspirin dosage on oxidative stress and platelet reactivity in patients undergoing coronary artery bypass grafting (APRICOT): randomized controlled trial.","authors":"Aleksandra Gąsecka, Rafał Kaczorowski, Katarzyna Pomykała, Tomasz Kucharski, Magdalena Gajewska, Dominika Siwik, Katarzyna Karoń, Maciej Małyszko, Jaromir Hunia, Jakub Michal Zimodro, Paweł Kowalczyk, Oliwia Zagrocka-Stendel, Małgorzata Dutkiewicz, Katarzyna Koziak, Ceren Eyileten, Marek Postuła, Mateusz Wondołkowski, Marcin Grabowski, Mariusz Kuśmierczyk, Radosław Wilimski","doi":"10.1080/09537104.2025.2457415","DOIUrl":"10.1080/09537104.2025.2457415","url":null,"abstract":"<p><p>Coronary artery bypass grafting (CABG) triggers oxidative stress and platelet activation. High acetylsalicylic acid (ASA) dose might mitigate the transient proinflammatory state. We compared the effect of three ASA dosages on post-CABG platelet reactivity, oxidative stress, and serum CD39 and CD73 levels. Thirty-six consecutive patients undergoing elective off-pump CABG, pre-treated with ASA 1 × 75 mg for ≥7 days, were randomized to continue the prior treatment regimen, switch to ASA 1 × 150 mg, or ASA 2 × 75 mg. Blood was collected on admission, 7 days, 1 month, and 3 months after CABG. Platelet reactivity was assessed using impedance aggregometry. Platelet oxidative stress was measured as platelet mitochondria extracellular oxygen consumption rate and oxidatively damaged whole-blood DNA cleavage. Serum CD39 and CD73 levels were determined using ELISA. Platelet reactivity and oxidative stress parameters were comparable in all groups. Patients treated with ASA 2 × 75 mg had higher CD39 levels at 7 days and 1 month (<i>p</i> = .049, <i>p</i> = .033), compared to the control group. ASA 2 × 75 mg was associated a beneficial effect on serum CD39 levels after off-pump CABG, without a significant effect on oxidative stress parameters.</p>","PeriodicalId":20268,"journal":{"name":"Platelets","volume":"36 1","pages":"2457415"},"PeriodicalIF":2.5,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143190154","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":"Immune-induced thrombocytopenia by pembrolizumab: case report and review of literature.","authors":"Nathan El-Ghazzi, Anna Monier, Antoine Italiano, Aude Besson, Eurydice Angeli","doi":"10.1080/09537104.2025.2487767","DOIUrl":"10.1080/09537104.2025.2487767","url":null,"abstract":"<p><p>Immune-checkpoint blockades (ICBs) are now used in early-stage diseases like triple-negative breast cancer (TNBC). While effective, they can cause severe toxicities. We report the first case of life-threatening immune thrombocytopenia (ITP) induced by pembrolizumab during neoadjuvant chemo-immunotherapy for early TNBC. A 42-year-old woman with early-stage TNBC developed grade 4 thrombocytopenia, diagnosed as ITP, after 107 days of pembrolizumab treatment. She required intensive care unit (ICU) admission and high-dose steroids, and intravenous immunoglobulin therapy, leading to a rapid recovery. ITP is a rare but potentially fatal complication of immunotherapy, with an incidence of less than 1% and a mortality rate of up to 20% in affected patients. Immediate recognition and steroid therapy are critical, as platelet transfusion is usually ineffective. Diagnosis is often delayed due to its similarity to chemotherapy-induced marrow toxicity. Immunotherapy-induced ITP generally contraindicates further use of the treatment. ITP, although uncommon, is a serious complication of immunotherapy requiring immediate intervention. The growing use of immunotherapy necessitates increased awareness of its potential toxicities among healthcare providers.</p>","PeriodicalId":20268,"journal":{"name":"Platelets","volume":"36 1","pages":"2487767"},"PeriodicalIF":2.5,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143773088","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":"Increased circulating platelet-derived extracellular vesicles in severe COVID-19 disease.","authors":"Tuukka Helin, Mari Palviainen, Marja Lemponen, Katariina Maaninka, Pia Siljander, Lotta Joutsi-Korhonen","doi":"10.1080/09537104.2024.2313362","DOIUrl":"10.1080/09537104.2024.2313362","url":null,"abstract":"<p><p>Coagulation disturbances are major contributors to COVID-19 pathogenicity, but limited data exist on the involvement of extracellular vesicles (EVs) and residual cells (RCs). Fifty hospitalized COVID-19 patients stratified by their D-dimer levels into high (>1.5 mg/L, <i>n</i> = 15) or low (≤1.5 mg/l, <i>n</i> = 35) and 10 healthy controls were assessed for medium-sized EVs (mEVs; 200-1000 nm) and large EVs/RCs (1000-4000 nm) by high sensitivity flow cytometry. EVs were analyzed for CD61, CD235a, CD45, and CD31, commonly used to detect platelets, red blood cells, leukocytes or endothelial cells, respectively, whilst phosphatidyl serine EVs/RCs were detected by lactadherin-binding implicating procoagulant catalytic surface. Small EV detection (sEVs; 50-200 nm) and CD41a (platelet integrin) colocalization with general EV markers CD9, CD63, and CD81 were performed by single particle interferometric reflectance imaging sensor. Patients with increased D-dimer exhibited the highest number of RCs and sEVs irrespective of cell origin (<i>p</i> < .05). Platelet activation, reflected by increased CD61+ and lactadherin+ mEV and RC levels, associated with coagulation disturbances. Patients with low D-dimer could be discriminated from controls by tetraspanin signatures of the CD41a+ sEVs, suggesting the changes in the circulating platelet sEV subpopulations may offer added prognostic value during COVID progression.</p>","PeriodicalId":20268,"journal":{"name":"Platelets","volume":"35 1","pages":"2313362"},"PeriodicalIF":3.3,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139913275","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":"Light transmission aggregometry for platelet function testing: position paper on current recommendations and French proposals for accreditation.","authors":"Alain Stépanian, Florence Fischer, Claire Flaujac, Valérie Eschwège, Céline Delassasseigne, Léna Leflem, Frédéric Loridon, Sophie Voisin, Dominique Lasne","doi":"10.1080/09537104.2024.2427745","DOIUrl":"10.1080/09537104.2024.2427745","url":null,"abstract":"<p><p>Light transmission aggregometry (LTA) is a method used to investigate platelet functions in platelet-rich plasma (PRP), notably when screening for platelet disorders. Various national guidelines and recommendations help in setting up the LTA test in specialized laboratories. However, due to the nature of the sample matrix and its subsequent specificities, more accurate positions are needed to achieve LTA accreditation according to the standard NF EN ISO 15 189. We reviewed guidelines and recommendations as they can be useful in the accreditation process, and we conducted a survey on LTA practice among members of the <i>Société Française de Thrombose et d'Hémostase (SFTH</i>) in 2021. We formulated 28 proposals, which have been approved by vote within the SFTH. All aspects to take into consideration for the proper conduct of LTA assays and their accreditation have been covered. Notably, preanalytical, analytical and postanalytical aspects are depicted, including blood sampling, PRP preparation, instruments, agonists, performance assessment, personnel training and data interpretation. This document, essentially representing a French position paper on the current recommendations and subsequent proposals for LTA accreditation, might prove useful also outside France for relevant laboratories and auditors involved in LTA accreditation.</p>","PeriodicalId":20268,"journal":{"name":"Platelets","volume":"35 1","pages":"2427745"},"PeriodicalIF":2.5,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142648580","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":"Appraising non-linear association between pre-diagnostic platelet counts and cancer survival outcomes: observational and genetic analysis.","authors":"Changtao Li, Junhua Chen, Deqian Han, Chi Shu, Jun Huang, Linru Wei, Haoran Luo, Qingbin Wu, Xin Chen, Yazhou He, Yanhong Zhou","doi":"10.1080/09537104.2024.2379815","DOIUrl":"https://doi.org/10.1080/09537104.2024.2379815","url":null,"abstract":"<p><p>Previous studies have reported inconsistent associations between platelet count (PLT) and cancer survival. However, whether there is linear causal effect merits in-depth investigations. We conducted a cohort study using the UK Biobank and a two-sample Mendelian randomization (MR) analysis. PLT levels were measured prior to cancer diagnosis. We adopted overall survival (OS) as the primary outcome. Cox models were utilized to estimate the effects of PLTs on survival outcomes at multiple lag times for cancer diagnosis. We employed 34 genetic variants as PLT proxies for MR analysis. Linear and non-linear effects were modeled. Prognostic effects of gene expression harboring the instrumental variants were also investigated. A total of 65 471 cancer patients were included. We identified a significant association between elevated PLTs (per 100 × 10⁹/L) and inferior OS (HR: 1.07; 95% CI: 1.04-1.10; <i>p</i> < .001). Similar significant associations were observed for several cancer types. We further observed a U-shaped relationship between PLTs and cancer survival (<i>p</i> < .001). Our MR analysis found null evidence to support a causal association between PLTs and overall cancer survival (HR: 1.000; 95% CI: 0.998-1.001; <i>p</i> = .678), although non-linear MR analysis unveiled a potential greater detrimental effect at lower PLT range. Expression of eleven PLT-related genes were associated with cancer survival. Early detection of escalated PLTs indicated possible occult cancer development and inferior subsequent survival outcomes. The observed associations could potentially be non-linear. However, PLT is less likely to be a promising therapeutic target.</p>","PeriodicalId":20268,"journal":{"name":"Platelets","volume":"35 1","pages":"2379815"},"PeriodicalIF":2.5,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141788892","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":"Exploring the morphine-platelet activity association in patients with ST-elevation myocardial infarction undergoing primary percutaneous coronary intervention.","authors":"Menikae K Heenkenda, Erik Träff, Tomas L Lindahl, Dimitrios Venetsanos, Joakim Alfredsson","doi":"10.1080/09537104.2024.2434225","DOIUrl":"https://doi.org/10.1080/09537104.2024.2434225","url":null,"abstract":"<p><p>ST-segment elevation myocardial infarction (STEMI) is usually caused by a ruptured atherosclerotic plaque, with subsequent thrombus formation. Platelet inhibition and primary percutaneous coronary intervention (PCI) are essential treatments. Morphine, used to relieve pain and anxiety in STEMI patients, delays the onset of P2Y12 inhibitors. This study aimed to further explore the association between platelet activity and morphine treatment in patients with STEMI. In this sub-study of the VALIDATE-SWEDHEART trial, 89 STEMI patients treated with ticagrelor, and primary PCI were included. Platelet aggregation and biomarkers of platelet activity, coagulation, and inflammation (sP-selectin, thrombin-antithrombin complexes, prothrombin fragments 1 + 2, CD40L, CRP, beta-thromboglobulin, and pentraxin3) were assessed at three time points: before, one, and twelve hours after PCI. Of the 89 patients, 40 received morphine before hospital arrival. There were no significant differences in age, sex, medical history, or coronary disease extent. One hour after PCI, ADP-induced (36 vs 61, <i>p</i> < .001), arachidonic acid-induced (20 vs 36, <i>p</i> = .003), collagen-induced (48 vs 60, <i>p</i> = .03) aggregation, and the proportion of high on-treatment ADP-induced platelet reactivity (27% vs 60%, <i>p</i> = .001) were significantly higher in morphine-treated patients. No significant differences were found before or 12 hours after PCI. No significant differences in platelet activity biomarkers were observed. Morphine increased platelet aggregation in STEMI patients but did not affect biomarkers.</p>","PeriodicalId":20268,"journal":{"name":"Platelets","volume":"35 1","pages":"2434225"},"PeriodicalIF":2.5,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142786698","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":"The efficacy of platelet rich plasma on women with poor ovarian response: a systematic review and meta-analysis.","authors":"Lingling Wu, Fenfang Su, Peixin Luo, Qingqing Dong, Mengni Ma, Guangyong Ye","doi":"10.1080/09537104.2023.2292612","DOIUrl":"10.1080/09537104.2023.2292612","url":null,"abstract":"<p><strong>Background: </strong>Platelet-rich plasma (PRP) is a therapeutic approach that is gaining attention for its potential in the treatment of poor ovarian response. This meta-analysis aimed to systematically review and analyze clinical studies to evaluate the impact of PRP on poor responders undergoing ovarian stimulation for IVF.</p><p><strong>Methods: </strong>A comprehensive search was conducted in electronic databases, including PubMed, Embase, Scopus, Web of Science, and the Cochrane Library to identify relevant studies published in English. The pooled data, such as pregnancy outcome, number of MII oocytes, number of transferable embryos, and ovarian reserve markers were analyzed using R version 4.2.3.</p><p><strong>Results: </strong>A total of 10 trials were enrolled in the present meta-analysis. Following PRP treatment, live birth rate was found to be 16.6% (95% CI 8.8%-26.1%), while clinical pregnancy rate was observed to be 25.4% (95% CI 13.1%-39.9%). PRP pretreatment resulted in a higher number of MII oocytes (MD 1.073, 95% CI 0.720 to 1.427), a higher number of embryos (MD 0.946, 95% CI 0.569 to 1.323), a higher antral follicle count (MD 1.117; 95% CI 0.689 to 1.544), and the change of hormone levels.</p><p><strong>Conclusions: </strong>Among the studies evaluated in this review, PRP showed promising results in poor responder. Further research is required to clarify the potential role of PRP in female reproductive health.</p>","PeriodicalId":20268,"journal":{"name":"Platelets","volume":"35 1","pages":"2292612"},"PeriodicalIF":3.3,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139425387","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}