NanotheranosticsPub Date : 2023-03-11eCollection Date: 2023-01-01DOI: 10.7150/ntno.82886
Amit Kumar Sharma
{"title":"Current Trends in Nanotheranostics: A Concise Review on Bioimaging and Smart Wearable Technology.","authors":"Amit Kumar Sharma","doi":"10.7150/ntno.82886","DOIUrl":"10.7150/ntno.82886","url":null,"abstract":"<p><p>The area of interventional nanotheranostics combines the use of interventional procedures with nanotechnology for the detection and treatment of physiological disorders. Using catheters or endoscopes, for example, interventional techniques make use of minimally invasive approaches to diagnose and treat medical disorders. It is feasible to increase the precision of these approaches and potency by integrating nanotechnology. To visualize and target various parts of the body, such as tumors or obstructed blood veins, one can utilize nanoscale probes or therapeutic delivery systems. Interventional nanotheranostics offers targeted, minimally invasive therapies that can reduce side effects and enhance patient outcomes, and it has the potential to alter the way that many medical illnesses are handled. Clinical enrollment and implementation of such laboratory scale theranostics approach in medical practice is promising for the patients where the user can benefit by tracking its physiological state. This review aims to introduce the most recent advancements in the field of clinical imaging and diagnostic techniques as well as newly developed on-body wearable devices to deliver therapeutics and monitor its due alleviation in the biological milieu.</p>","PeriodicalId":36934,"journal":{"name":"Nanotheranostics","volume":"7 3","pages":"258-269"},"PeriodicalIF":0.0,"publicationDate":"2023-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10093415/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9386894","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Emergence of Raman Spectroscopy as a Probing Tool for Theranostics.","authors":"Ruchi Singh, Vikas Yadav, Ashish Kumar Dhillon, Arti Sharma, Tripti Ahuja, Soumik Siddhanta","doi":"10.7150/ntno.81936","DOIUrl":"10.7150/ntno.81936","url":null,"abstract":"<p><p>Although medical advances have increased our grasp of the amazing morphological, genetic, and phenotypic diversity of diseases, there are still significant technological barriers to understanding their complex and dynamic character. Specifically, the complexities of the biological systems throw a diverse set of challenges in developing efficient theranostic tools and methodologies that can probe and treat pathologies. Among several emerging theranostic techniques such as photodynamic therapy, photothermal therapy, magnetic resonance imaging, and computed tomography, Raman spectroscopy (RS) is emerging as a promising tool that is a label-free, cost-effective, and non-destructive technique. It can also provide real-time diagnostic information and can employ multimodal probes for detection and therapy. These attributes make it a perfect candidate for the analytical counterpart of the existing theranostic probes. The use of biocompatible nanomaterials for the fabrication of Raman probes provides rich structural information about the biological molecules, cells, and tissues and highly sensitive information down to single-molecule levels when integrated with advanced RS tools. This review discusses the fundamentals of Raman spectroscopic tools such as surface-enhanced Raman spectroscopy and Resonance Raman spectroscopy, their variants, and the associated theranostic applications. Besides the advantages, the current limitations, and future challenges of using RS in disease diagnosis and therapy have also been discussed.</p>","PeriodicalId":36934,"journal":{"name":"Nanotheranostics","volume":"7 3","pages":"216-235"},"PeriodicalIF":0.0,"publicationDate":"2023-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10093420/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9331876","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
NanotheranosticsPub Date : 2023-02-05eCollection Date: 2023-01-01DOI: 10.7150/ntno.81724
Vivek P Chavda, Pankti C Balar, Srushti B Patel
{"title":"Nanotheranostics-based Management of Head and Neck Cancer.","authors":"Vivek P Chavda, Pankti C Balar, Srushti B Patel","doi":"10.7150/ntno.81724","DOIUrl":"10.7150/ntno.81724","url":null,"abstract":"<p><p>Head and neck cancer is affecting a large sort of population. Many treatments are available on a regular base, but they have their limitations. Diagnosis in the early stage is essential to cope with the disease which is a limitation in the majority of present diagnostic tools. Many of them are invasive methods that lead to patient discomfort. Interventional nanothernostics is an emerging field in the management of Head and Neck cancer. It facilitates both diagnostic and therapeutic approaches. It also helps with the overall management of the disease. This method allows the early and accurate detection of the disease which improvises the chances of recovery. Additionally, it makes sure that the medicine is delivered specifically to increase clinical outcomes and reduce side effects. The use of radiation in addition to the medicine supplied can produce a synergistic effect. It contains several nanoparticles, including silicon and gold nanoparticles. This review paper focuses on the shortcomings of existing therapeutic techniques and how nanotheranostics fills the void.</p>","PeriodicalId":36934,"journal":{"name":"Nanotheranostics","volume":"7 2","pages":"202-209"},"PeriodicalIF":0.0,"publicationDate":"2023-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9925351/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10851676","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
NanotheranosticsPub Date : 2023-01-09eCollection Date: 2023-01-01DOI: 10.7150/ntno.80120
Vivek P Chavda, Pankti C Balar, Srushti B Patel
{"title":"Interventional nanotheranostics in hepatocellular carcinoma.","authors":"Vivek P Chavda, Pankti C Balar, Srushti B Patel","doi":"10.7150/ntno.80120","DOIUrl":"10.7150/ntno.80120","url":null,"abstract":"<p><p>Interventional nanotheranostics is a system of drug delivery that does a dual function; along with the therapeutic action, it also does have diagnostic features. This method helps in early detection, targeted delivery, and the least chances of damage to surrounding tissue. It ensures the highest efficiency for the management of the disease. Imaging is the near future for the quickest and most accurate detection of disease. After combing both effective measures, it ensures the most meticulous drug delivery system. Nanoparticles such as Gold NPs, Carbon NPs, Silicon NPS, etc. The article emphasizes on effect of this delivery system in the treatment of Hepatocellular Carcinoma. It is one of the widely spreading diseases and theranostics is trying to make the scenario better. The review suggests the pitfall of the current system and how theranostics can help. It describes the mechanism used to generate its effect and believes that interventional nanotheranostics do have a future with rainbow color. The article also describes the current hindrance to the flourishing of this miraculous technology.</p>","PeriodicalId":36934,"journal":{"name":"Nanotheranostics","volume":"7 2","pages":"128-141"},"PeriodicalIF":0.0,"publicationDate":"2023-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9925354/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10842961","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Priya Patel, Areej Alghamdi, Gary Shaw, Christopher Legge, Maggie Glover, Danielle Freeman, Harry Hodgetts, Erica Wilson, Faith Howard, Sarah Staniland, Aneurin J Kennerley, Duncan Wood, Robert Moorehead, Charlotte Hadfield, Ola Rominiyi, Jon Griffin, Spencer J Collis, Sam Hyde, Marcus Crossley, Martyn Paley, Munitta Muthana
{"title":"Development of a Personalised Device for Systemic Magnetic Drug Targeting to Brain Tumours.","authors":"Priya Patel, Areej Alghamdi, Gary Shaw, Christopher Legge, Maggie Glover, Danielle Freeman, Harry Hodgetts, Erica Wilson, Faith Howard, Sarah Staniland, Aneurin J Kennerley, Duncan Wood, Robert Moorehead, Charlotte Hadfield, Ola Rominiyi, Jon Griffin, Spencer J Collis, Sam Hyde, Marcus Crossley, Martyn Paley, Munitta Muthana","doi":"10.7150/ntno.76559","DOIUrl":"10.7150/ntno.76559","url":null,"abstract":"<p><p>Delivering therapies to deeply seated brain tumours (BT) is a major clinical challenge. Magnetic drug targeting (MDT) could overcome this by rapidly transporting magnetised drugs directly into BT. We have developed a magnetic device for application in murine BT models using an array of neodymium magnets with a combined strength of 0.7T. In a closed fluidic system, the magnetic device trapped magnetic nanoparticles (MNP) up to distances of 0.8cm. In mice, the magnetic device guided intravenously administered MNP (<50nm) from the circulation into the brain where they localised within mouse BT. Furthermore, MDT of magnetised Temozolomide (TMZ<sup>mag+</sup>) significantly reduced tumour growth and extended mouse survival to 48 days compared to the other treatment groups. Using the same principles, we built a proof of principle scalable magnetic device for human use with a strength of 1.1T. This magnetic device demonstrated trapping of MNP undergoing flow at distances up to 5cm. MDT using our magnetic device provides an opportunity for targeted delivery of magnetised drugs to human BT.</p>","PeriodicalId":36934,"journal":{"name":"Nanotheranostics","volume":"7 1","pages":"102-116"},"PeriodicalIF":0.0,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9760367/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9195277","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Engineering molecular nanoprobes to target early atherosclerosis: Precise diagnostic tools and promising therapeutic carriers.","authors":"Chunfang Zan, Jie An, Zhifang Wu, Sijin Li","doi":"10.7150/ntno.82654","DOIUrl":"https://doi.org/10.7150/ntno.82654","url":null,"abstract":"<p><p>Atherosclerosis, an inflammation-driven chronic blood vessel disease, is a major contributor to devastating cardiovascular events, bringing serious social and economic burdens. Currently, non-invasive diagnostic and therapeutic techniques in combination with novel nanosized materials as well as established molecular targets are under active investigation to develop integrated molecular imaging approaches, precisely visualizing and/or even effectively reversing early-stage plaques. Besides, mechanistic investigation in the past decades provides many potent candidates extensively involved in the initiation and progression of atherosclerosis. Recent hotly-studied imaging nanoprobes for detecting early plaques mainly including optical nanoprobes, photoacoustic nanoprobes, magnetic resonance nanoprobes, positron emission tomography nanoprobes, and other dual- and multi-modality imaging nanoprobes, have been proven to be surface functionalized with important molecular targets, which occupy tailored physical and biological properties for atherogenesis. Of note, these engineering nanoprobes provide long blood-pool residence and specific molecular targeting, which allows efficient recognition of early-stage atherosclerotic plaques and thereby function as a novel type of precise diagnostic tools as well as potential therapeutic carriers of anti-atherosclerosis drugs. There have been no available nanoprobes applied in the clinics so far, although many newly emerged nanoprobes, as exemplified by aggregation-induced emission nanoprobes and TiO<sub>2</sub> nanoprobes, have been tested for cell lines <i>in vitro</i> and atherogenic animal models <i>in vivo</i>, achieving good experimental effects. Therefore, there is an urgent call to translate these preclinical results for nanoprobes into clinical trials. For this reason, this review aims to give an overview of currently investigated nanoprobes in the context of atherosclerosis, summarize relevant published studies showing applications of different kinds of formulated nanoprobes in early detection and reverse of plaques, discuss recent advances and some limitations thereof, and provide some insights into the development of the new generation of more precise and efficient molecular nanoprobes, with a critical property of specifically targeting early atherosclerosis.</p>","PeriodicalId":36934,"journal":{"name":"Nanotheranostics","volume":"7 3","pages":"327-344"},"PeriodicalIF":0.0,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10093416/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9331869","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Dhananjie Chandrasekera, Rishi Shah, Isabelle van Hout, Willow De Jonge, Richard Bunton, Dominic Parry, Philip Davis, Rajesh Katare
{"title":"Combination of precipitation and size exclusion chromatography as an effective method for exosome like extracellular vesicle isolation from pericardial fluids.","authors":"Dhananjie Chandrasekera, Rishi Shah, Isabelle van Hout, Willow De Jonge, Richard Bunton, Dominic Parry, Philip Davis, Rajesh Katare","doi":"10.7150/ntno.82939","DOIUrl":"https://doi.org/10.7150/ntno.82939","url":null,"abstract":"<p><p>Extracellular vesicles (EVs), such as exosomes, are nanovesicles that have received significant attention due to their ability to contain various molecular cargos. EVs found in biological fluids have been demonstrated to have therapeutic potential, including as biomarkers. Despite being extensively studied, a significant downfall in EV research is the lack of standardised protocol for its isolation from human biological fluids, where EVs usually exist at low densities. In this study, we tested two well-established EV isolation protocols, precipitation, and size exclusion chromatography (SEC), to determine their efficiency in isolating EVs from the pericardial fluid. Precipitation alone resulted in high yields of low-purity exosomes as tested by DLS analysis, transmission electron microscopy, immunogold labelling and western blotting for the exosomal surface proteins. While EVs isolated by SEC were pure, the concentration was low. Interestingly, the combination of precipitation followed by SEC resulted in high EV yields with good purity. Our results suggest that the combination method can be adapted to isolate EVs from body fluids which have low densities of EV.</p>","PeriodicalId":36934,"journal":{"name":"Nanotheranostics","volume":"7 4","pages":"345-352"},"PeriodicalIF":0.0,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10161387/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10139909","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Murlidhar A Betallu, Shaileshkumar R Bhalara, Kailash B Sapnar, Vijay B Tadke, Keerti Meena, Ananya Srivastava, Gopal C Kundu, Mahadeo Gorain
{"title":"Hybrid Inorganic Complexes as Cancer Therapeutic Agents: In-vitro Validation.","authors":"Murlidhar A Betallu, Shaileshkumar R Bhalara, Kailash B Sapnar, Vijay B Tadke, Keerti Meena, Ananya Srivastava, Gopal C Kundu, Mahadeo Gorain","doi":"10.7150/ntno.81557","DOIUrl":"https://doi.org/10.7150/ntno.81557","url":null,"abstract":"<p><p>A series of novel mixed transition metal-Magnesium tartarate complexes of general formulation [MMg(C<sub>4</sub>H<sub>4</sub>O<sub>6</sub>)<sub>2</sub> <sup>.</sup>xH<sub>2</sub>O] (where M = Mn, Fe, Co, Ni, Cu and Zn) is prepared with bidentate tartarate ligand. The synthesized complexes (C1 to C6) are characterized by various analytical techniques such as Elemental analysis, Thermo gravimetric analysis, FT-IR Spectroscopy, X-ray Diffraction, Magnetic susceptibility study etc. All complexes exhibit the composition MMgL<sub>2</sub> where M = Mn(II), Fe(II), Co(II), Ni(II), Cu(II) and Zn(II) and L = bidentate tartarate ligand. Analytical data reveals all complexes possesses 1:1 (metal: ligand) ratio. FT-IR spectral study shows that bidentate tartarate ligand coordinate with metal ion in a bidentate manner through two oxygen atoms. Thermo gravimetric analysis of all complexes shows that degradation curves of complexes agrees with recommended formulae of the complexes. X-ray diffraction technique suggests that all complexes (C1 to C6) are polycrystalline in nature. All newly synthesized metal tartarate complexes and ligand were screened <i>in vitro</i> for their anticancer activity against human breast cancer (MDA-MB-231) cell line. The bioassays of all these complexes showed C3 (Co) and C5 (Cu) Mg-tartarate complexes contains maximum antiproliferative activity at 200 µg/ml concentration on MDA-MB-231 cells as compared to other complexes. MDA-MB-231 cells treated with C3 (Co) and C5 (Cu) Mg-tartarate complexes also showed inhibition in cell migration.</p>","PeriodicalId":36934,"journal":{"name":"Nanotheranostics","volume":"7 3","pages":"270-280"},"PeriodicalIF":0.0,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10093419/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9386899","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Ultra-small NIR-Responsive Nanotheranostic Agent for Targeted Photothermal Ablation Induced Damage-Associated Molecular Patterns (DAMPs) from Post-PTT of Tumor Cells Activate Immunogenic Cell Death.","authors":"Shankar Sobhana, Namratha Partha Sarathy, Laxmanan Karthikeyan, Krishnamurthy Shanthi, Raju Vivek","doi":"10.7150/ntno.76720","DOIUrl":"https://doi.org/10.7150/ntno.76720","url":null,"abstract":"<p><p>Theranostic nanoparticles (TNPs) is an efficient avenue that culminates both diagnosis and therapy into cancer treatment. Herein, we have formulated a theranostic nanocomposite (NC) with CuS being the ultra-small core component. To ensure stability to the NC, PEI was added which is a vital anchoring group polymer, especially on sulfide surfaces, and adds quality by being a better stabilizer and reducing agent. Additionally, to add stability, specificity, and added photothermal efficiency to the fabricated NC. In addition, encapsulation of indocyanine green (ICG), an efficient NIR absorber, and Folic acid (FA) were conjugated systematically, characterized, and analyzed for photo-stability. The photothermal conversion efficiency of the novel NC (CuS-PEI-ICG-FA) was analyzed at 808 nm, where the NC efficiently converted light energy to heat energy. The NC was also tested for hemocompatibility to clarify and also determined biocompatibility. Surprisingly, damage-associated molecular patterns (DAMPs) from post-PTT of tumor cells activate immunogenic cell death (ICD) for tumor-specific immune responses. The deserving photothermal performance and photo-stability makes the NC an ideal platform for photoacoustic imaging (PAI). A superior contrast was observed for PAI in a concentration-dependent manner enhancing the level of penetration into tissues, thereby better imaging. On account of this study, the newly formulated NC could be utilized as a <b>\"<i>nanotheranostic</i>\"</b> designed for therapeutic and image diagnostic agent of cancer biomedical applications.</p>","PeriodicalId":36934,"journal":{"name":"Nanotheranostics","volume":"7 1","pages":"41-60"},"PeriodicalIF":0.0,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9760365/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10701875","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Elham Ahmadian, Aziz Eftekhari, Dawid Janas, Parviz Vahedi
{"title":"Nanofiber scaffolds based on extracellular matrix for articular cartilage engineering: A perspective.","authors":"Elham Ahmadian, Aziz Eftekhari, Dawid Janas, Parviz Vahedi","doi":"10.7150/ntno.78611","DOIUrl":"https://doi.org/10.7150/ntno.78611","url":null,"abstract":"<p><p>Articular cartilage has a low self-repair capacity due to the lack of vessels and nerves. In recent times, nanofiber scaffolds have been widely used for this purpose. The optimum nanofiber scaffold should stimulate new tissue's growth and mimic the articular cartilage nature. Furthermore, the characteristics of the scaffold should match those of the cellular matrix components of the native tissue to best merge with the target tissue. Therefore, selective modification of prefabricated scaffolds based on the structure of the repaired tissues is commonly conducted to promote restoring the tissue. A thorough analysis is required to find out the architectural features of scaffolds that are essential to make the treatment successful. The current review aims to target this challenge. The article highlights different optimization approaches of nanofibrous scaffolds for improved cartilage tissue engineering. In this context, the influence of the architecture of nanoscaffolds on performance is discussed in detail. Finally, based on the gathered information, a future outlook is provided to catalyze development in this promising field.</p>","PeriodicalId":36934,"journal":{"name":"Nanotheranostics","volume":"7 1","pages":"61-69"},"PeriodicalIF":0.0,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9760364/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10701874","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}