Pharmacological research最新文献

{"title":"Impact of Sodium-glucose cotransporter 2 inhibitors (SGLT2i) and other antidiabetic agents in Alzheimer’s disease","authors":"Ju-Ching Yen , Jia-Yu Lai , Chi-Ya Yang, Su-Boon Yong, Chin-Yuan Yii","doi":"10.1016/j.phrs.2024.107473","DOIUrl":"10.1016/j.phrs.2024.107473","url":null,"abstract":"","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"209 ","pages":"Article 107473"},"PeriodicalIF":9.1,"publicationDate":"2024-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142472153","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeted and cytotoxic inhibitors used in the treatment of lung cancers","authors":"Robert Roskoski Jr.","doi":"10.1016/j.phrs.2024.107465","DOIUrl":"10.1016/j.phrs.2024.107465","url":null,"abstract":"<div><div>Lung cancer is the leading cause of cancer deaths in the United States and the world. It is divided into two major types: small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC). In the tumor-node-metastasis (TNM) cancer-staging classification system (Stages I/II/III/IV), the severity of neoplastic growth is characterized by the size of the tumor (T1 to T4), the extent of lymph node involvement (N0 to N3), and whether (M1) or not (M0) distant metastasis has occurred. Surgery is the treatment of choice for medically fit patients with Stage I/II NSCLC. Combination chemoradiotherapy and immune checkpoint inhibitor therapy are used across all NSCLC types. Oncogene-addicted tumors with sensitizing <em>EGFR</em> or <em>BRAF</em> mutations or activating <em>ALK</em>, <em>ROS1</em> or <em>NTRK</em> translocations are treated with their cognate orally active small molecule protein kinase blockers. On the order of 20 % of NSCLCs bear activating mutations in <em>EGFR</em> and are treated with osimertinib and other kinase antagonists. SCLC, which accounts for approximately 15 % of lung cancer cases, is a deadly high-grade neuroendocrine carcinoma with a poor prognosis. Limited-stage SCLC is confined to one hemi-thorax and one radiation port and extensive-stage disease signifies those cancers that do not meet the criteria for limited-stage disease. Local treatment options to control thoracic disease include radiotherapy and surgery. In patients with extensive-stage disease, a platinum agent (cisplatin or carboplatin) combined with etoposide and an anti-PDL1 inhibitor (atezolizumab or durvalumab) for four cycles followed by anti-PDL1 maintenance therapy is the recommended first-line regimen.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"209 ","pages":"Article 107465"},"PeriodicalIF":9.1,"publicationDate":"2024-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142472159","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Therapeutic peptides in the treatment of digestive inflammation: Current advances and future prospects","authors":"Liangliang He ,&nbsp;Aijing Li ,&nbsp;Ping Yu ,&nbsp;Shumin Qin ,&nbsp;Hor-Yue Tan ,&nbsp;Denglang Zou ,&nbsp;Haomeng Wu ,&nbsp;Shuai Wang","doi":"10.1016/j.phrs.2024.107461","DOIUrl":"10.1016/j.phrs.2024.107461","url":null,"abstract":"<div><div>Digestive inflammation is a widespread global issue that significantly impacts quality of life. Recent advances have highlighted the unique potential of therapeutic peptides for treating this condition, owing to their specific bioactivity and high specificity. By specifically targeting key proteins involved in the pathological process and modulating biomolecular functions, therapeutic peptides offer a novel and promising approach to managing digestive inflammation. This review explores the development history, pharmacological characteristics, clinical applications, and regulatory mechanisms of therapeutic peptides in treating digestive inflammation. Additionally, the review addresses pharmacokinetics and quality control methods of therapeutic peptides, focusing on challenges such as low bioavailability, poor stability, and difficulties in delivery. The role of modern biotechnologies and nanotechnologies in overcoming these challenges is also examined. Finally, future directions for therapeutic peptides and their potential impact on clinical applications are discussed, with emphasis placed on their significant role in advancing medical and therapeutic practices.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"209 ","pages":"Article 107461"},"PeriodicalIF":9.1,"publicationDate":"2024-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142472161","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The PINK1/Parkin signaling pathway-mediated mitophagy: a forgotten protagonist in myocardial ischemia/reperfusion injury","authors":"Xiaopeng Zhao ,&nbsp;Zheng Wang ,&nbsp;Lijie Wang ,&nbsp;Tao Jiang ,&nbsp;Dan Dong ,&nbsp;Mingli Sun","doi":"10.1016/j.phrs.2024.107466","DOIUrl":"10.1016/j.phrs.2024.107466","url":null,"abstract":"<div><div>Myocardial ischemia causes extensive damage, further exacerbated by reperfusion, a phenomenon called myocardial ischemia/reperfusion injury (MIRI). Nowadays, the pathological mechanisms of MIRI have received extensive attention. Oxidative stress, multiple programmed cell deaths, inflammation and others are all essential pathological mechanisms contributing to MIRI. Mitochondria are the energy supply centers of cells. Numerous studies have found that abnormal mitochondrial function is an essential \"culprit\" of MIRI, and mitophagy mediated by the phosphatase and tensin homolog (PTEN)-induced kinase 1 (PINK1)/Parkin signaling pathway is an integral part of maintaining mitochondrial function. Therefore, exploring the association between the PINK1/Parkin signaling pathway-mediated mitophagy and MIRI is crucial. This review will mainly summarize the crucial role of the PINK1/Parkin signaling pathway-mediated mitophagy in MIR-induced several pathological mechanisms and various potential interventions that affect the PINK1/Parkin signaling pathway-mediated mitophagy, thus ameliorating MIRI.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"209 ","pages":"Article 107466"},"PeriodicalIF":9.1,"publicationDate":"2024-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142472160","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Ex vivo fluorescence-guided resection margin assessment in breast cancer surgery using a topically applied, cathepsin-activatable imaging agent","authors":"Daan G.J. Linders ,&nbsp;Okker D. Bijlstra ,&nbsp;Ethan Walker ,&nbsp;Taryn L. March ,&nbsp;Martin Pool ,&nbsp;A. Rob P.M. Valentijn ,&nbsp;Tom H. Dijkhuis ,&nbsp;Jikke N. Woltering ,&nbsp;Floor R. Pijl ,&nbsp;Gilbert Noordam ,&nbsp;Davey van den Burg ,&nbsp;Joost R.M. van der Sijp ,&nbsp;Onno R. Guicherit ,&nbsp;Andreas W.K.S. Marinelli ,&nbsp;Jacobus Burggraaf ,&nbsp;Robert Rissmann ,&nbsp;Matthew Bogyo ,&nbsp;Denise E. Hilling ,&nbsp;Peter J.K. Kuppen ,&nbsp;Brian Straight ,&nbsp;Alexander L. Vahrmeijer","doi":"10.1016/j.phrs.2024.107464","DOIUrl":"10.1016/j.phrs.2024.107464","url":null,"abstract":"<div><div>Up to 40 % of breast cancer patients have a tumor-positive resection margin (TPRM) – defined as cancer cells at the surface of the resected specimen – after breast-conserving surgery (BCS), necessitating re-resection or boost radiation. To prevent these additional treatments, intraoperative near-infrared (NIR) fluorescence imaging with the topically applied, cathepsin-activatable imaging agent AKRO-6qcICG might be used to detect TPRMs and guide additional resection. Here, to validate its performance, the agent is topically applied to all surfaces of freshly resected breast cancer specimens (<em>n =</em> 11 patients) and to 3–5 mm thick tissue slices of the specimens (n = 26 patients). NIR fluorescence images of the resection surfaces and tissue slices are acquired and correlated to final histopathology. AKRO-6qcICG detects TPRMs with a sensitivity, specificity, PVV, and NPV of 100 %, 67 %, 10 %, and 100 %, respectively. On the tissue slices, the fluorescence signal has a median tumor-to-background ratio of 1.8. These findings indicate that topically applied AKRO-6qcICG can visualize TPRMs <em>ex vivo</em> with a high sensitivity and NPV, with sufficient contrast to adjacent healthy breast tissue.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"209 ","pages":"Article 107464"},"PeriodicalIF":9.1,"publicationDate":"2024-10-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142442904","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Excessive alcohol intake produces persistent mechanical allodynia and dysregulates the endocannabinoid system in the lumbar dorsal root ganglia of genetically-selected Marchigian Sardinian alcohol-preferring rats","authors":"Vittoria Borgonetti ,&nbsp;Valentina Vozella ,&nbsp;Tim Ware ,&nbsp;Bryan Cruz ,&nbsp;Ryan Bullard ,&nbsp;Benjamin F. Cravatt ,&nbsp;Nicoletta Galeotti ,&nbsp;Marisa Roberto","doi":"10.1016/j.phrs.2024.107462","DOIUrl":"10.1016/j.phrs.2024.107462","url":null,"abstract":"<div><div>Epidemiological data indicate a strong association between alcohol use disorder (AUD) and neuropathic pain. Genetically-selected Marchigian Sardinian alcohol-preferring (msP) rats exhibit a high preference for alcohol compared with their background strain (Wistar rats), but their sensitivity to mechanical allodynia after chronic alcohol exposure is unknown. The present study compared the development of mechanical allodynia between “low, non-pathological drinker” Wistar rats and “high drinker” msP rats using the two-bottle choice (2BC) free-access procedure. Several studies reported the involvement of endocannabinoids (eCBs) in modulating mechanical allodynia, but there are no data on their role in alcohol-related allodynia. Thus, the present study assessed eCBs and their related lipid species in lumbar dorsal root ganglia (DRG) and correlated them with mechanical allodynia in our model. We found that male and female msP rats developed persistent mechanical allodynia during protracted abstinence from alcohol, presenting no sign of recovery, as opposed to Wistar rats. This effect directly correlated with their total alcohol intake. Notably, we found a correlation between lower lumbar DRG 2-arachidonoylglycerol (2-AG) levels and the development of higher mechanical allodynia during abstinence in msP rats of both sexes but not in Wistar rats. Moreover, alcohol-exposed and abstinent msP and Wistar females but not males exhibited significant alterations of thromboxane B2 and prostaglandin E2/prostaglandin D2 compared with naive rats. These findings demonstrate that DRG 2-AG metabolism is altered in msP rats during prolonged abstinence and represents a potentially interesting pharmacological target for the treatment of mechanical allodynia during alcohol abstinence.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"209 ","pages":"Article 107462"},"PeriodicalIF":9.1,"publicationDate":"2024-10-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142442905","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Baseline gut microbiome as a predictive biomarker of response to probiotic adjuvant treatment in gout management","authors":"Feiyan Zhao ,&nbsp;Ning Tie ,&nbsp;Lai-Yu Kwok ,&nbsp;Teng Ma ,&nbsp;Jing Wang ,&nbsp;Dafu Man ,&nbsp;Xiangzheng Yuan ,&nbsp;Huiyun Li ,&nbsp;Lixia Pang ,&nbsp;Hui Shi ,&nbsp;Shuiming Ren ,&nbsp;Zhongjie Yu ,&nbsp;Xin Shen ,&nbsp;Hongbin Li ,&nbsp;Heping Zhang","doi":"10.1016/j.phrs.2024.107445","DOIUrl":"10.1016/j.phrs.2024.107445","url":null,"abstract":"<div><div>Gout is characterized by dysregulation of uric acid (UA) metabolism, and the gut microbiota may serve as a regulatory target. This two-month randomized, double-blind, placebo-controlled trial aimed to investigate the additional benefits of coadministering Probio-X alongside febuxostat. A total of 160 patients with gout were randomly assigned to either the probiotic group (n = 120; Probio-X [1 ×10¹¹ CFU/day] with febuxostat) or the placebo group (n = 40; placebo material with febuxostat). Coadministration of Probio-X significantly decreased serum UA levels and the rate of acute gout attacks (<em>P</em> &lt; 0.05). Based on achieving a target sUA level (360 μmol/L) after the intervention, the probiotic group was further subdivided into probiotic-responsive (ProA; n = 54) and probiotic-unresponsive (ProB; n = 66) subgroups. Post-intervention clinical indicators, metagenomic, and metabolomic changes in the ProB and placebo groups were similar, but differed from those in the ProA group, which exhibited significantly lower levels of acute gout attack, gout impact score, serum indicators (UA, XOD, hypoxanthine, and IL-1β), and fecal gene abundances of UA-producing pathways (KEGG orthologs of K13479 and K01487; gut metabolic modules for formate conversion and lactose and galactose degradation). Additionally, the ProA group showed significantly higher levels (<em>P</em> &lt; 0.05) of gut SCFAs-producing bacteria and UA-related metabolites (xanthine, hypoxanthine, bile acids) after the intervention. Finally, we established a gout metagenomic classifier to predict probiotic responsiveness based on subjects’ baseline gut microbiota composition. Our results indicate that probiotic-driven therapeutic responses are highly individual, with the probiotic-responsive cohort benefitting significantly from probiotic coadministration.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"209 ","pages":"Article 107445"},"PeriodicalIF":9.1,"publicationDate":"2024-10-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142433404","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Efficacy of medications for the treatment of alcohol use disorder (AUD): A systematic review and meta-analysis considering baseline AUD severity","authors":"Roberta Agabio ,&nbsp;Hugo Lopez-Pelayo ,&nbsp;Pol Bruguera ,&nbsp;San-Yuan Huang ,&nbsp;Salvatore Sardo ,&nbsp;Marta Pecina ,&nbsp;Evgeny M. Krupitsky ,&nbsp;Garrett M. Fitzmaurice ,&nbsp;Zhicheng Lin","doi":"10.1016/j.phrs.2024.107454","DOIUrl":"10.1016/j.phrs.2024.107454","url":null,"abstract":"<div><div>Baseline severity of alcohol use disorder (AUD) is an influencing factor in the response to medications recommended for the treatment of AUD. The scarce efficacy of AUD medications partly justifies their limited uses. We were interested in evaluating the efficacy of approved and recommended AUD medications using generic inverse-variance, an analysis facilitating comparison between medications and placebo both at the end of the study and, concomitantly, to baseline values for the same participants. We conducted a systematic review to include randomized controlled trials (RCTs) comparing any medication to placebo providing, both at baseline and end of treatment, percent heavy drinking days (%HDD), percent drinking days (%DD), and/or drinks per drinking day (DDD). We searched PubMed, Embase, PMC, and three CT registers from inception to April 2023. A total of 79 RCTs (11,737 AUD participants; 30 different medications) were included: 47 RCTs (8465 participants) used AUD medications, and 32 RCTs (3272 participants) used other medications. At baseline, participants consumed on average approximately 12 DDD, and experienced 70 % DD, and 61 % HDD. Placebo halved or reduced these values to a third. Compared to placebo, AUD medications further reduced these outcomes (moderate to high certainty evidence). Other medications reduced the DDD without modifying other alcohol outcomes. AUD medications increased the risk of developing adverse events (high-certainty evidence). Despite the large placebo effects, our results support the benefits of providing AUD medications to people with AUD, helping them reduce alcohol consumption.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"209 ","pages":"Article 107454"},"PeriodicalIF":9.1,"publicationDate":"2024-10-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142433403","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Enhanced drug classification using machine learning with multiplexed cardiac contractility assays","authors":"Reza Aghavali,&nbsp;Erin G. Roberts,&nbsp;Yosuke K. Kurokawa,&nbsp;Erica Mak,&nbsp;Martin Y.C. Chan,&nbsp;Andy O.T. Wong,&nbsp;Ronald A. Li,&nbsp;Kevin D. Costa","doi":"10.1016/j.phrs.2024.107459","DOIUrl":"10.1016/j.phrs.2024.107459","url":null,"abstract":"<div><div>Cardiac screening of newly discovered drugs remains a longstanding challenge for the pharmaceutical industry. While therapeutic efficacy and cardiotoxicity are evaluated through preclinical biochemical and animal testing, 90 % of lead compounds fail to meet safety and efficacy benchmarks during human clinical trials. A preclinical model more representative of the human cardiac response is needed; heart tissue engineered from human pluripotent stem cell derived cardiomyocytes offers such a platform. In this study, three functionally distinct and independently validated engineered cardiac tissue assays are exposed to increasing concentrations of known compounds representing 5 classes of mechanistic action, creating a robust electrophysiology and contractility dataset. Combining results from six individual models, the resulting ensemble algorithm can classify the mechanistic action of unknown compounds with 86.2 % predictive accuracy. This outperforms single-assay models and offers a strategy to enhance future clinical trial success aligned with the recent FDA Modernization Act 2.0.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"209 ","pages":"Article 107459"},"PeriodicalIF":9.1,"publicationDate":"2024-10-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142472155","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The role of Tim-3 blockade in the tumor immune microenvironment beyond T cells","authors":"Jie Zhang ,&nbsp;Longsheng Wang ,&nbsp;Hongjie Guo ,&nbsp;Shijia Kong ,&nbsp;Wen Li ,&nbsp;Qiaojun He ,&nbsp;Ling Ding ,&nbsp;Bo Yang","doi":"10.1016/j.phrs.2024.107458","DOIUrl":"10.1016/j.phrs.2024.107458","url":null,"abstract":"<div><div>Numerous preclinical studies have demonstrated the inhibitory function of T cell immunoglobulin mucin domain-containing protein 3 (Tim-3) on T cells as an inhibitory receptor, leading to the clinical development of anti-Tim-3 blocking antibodies. However, recent studies have shown that Tim-3 is expressed not only on T cells but also on multiple cell types in the tumor microenvironment (TME), including dendritic cells (DCs), natural killer (NK) cells, macrophages, and tumor cells. Therefore, Tim-3 blockade in the immune microenvironment not only affect the function of T cells but also influence the functions of other cells. For example, Tim-3 blockade can enhance the ability of DCs to regulate innate and adaptive immunity. The role of Tim-3 blockade in NK cells function is controversial, as it can enhance the antitumor function of NK cells under certain conditions while having the opposite effect in other situations. Additionally, Tim-3 blockade can promote the reversal of macrophage polarization from the M2 phenotype to the M1 phenotype. Furthermore, Tim-3 blockade can inhibit tumor development by suppressing the proliferation and metastasis of tumor cells. In summary, increasing evidence has shown that Tim-3 in other cell types also plays a critical role in the efficacy of anti-Tim-3 therapy. Understanding the function of anti-Tim-3 therapy in non-T cells can help elucidate the diverse responses observed in clinical patients, leading to better development of relevant therapeutic strategies. This review aims to discuss the role of Tim-3 in the TME and emphasize the impact of Tim-3 blockade in the tumor immune microenvironment beyond T cells.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"209 ","pages":"Article 107458"},"PeriodicalIF":9.1,"publicationDate":"2024-10-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142433402","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}