{"title":"巻頭言","authors":"弘一 三宅","doi":"10.1272/manms.19.198","DOIUrl":"https://doi.org/10.1272/manms.19.198","url":null,"abstract":"","PeriodicalId":35560,"journal":{"name":"Journal of Tokyo Medical University","volume":"9 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-08-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"135989963","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"学生支援からメタバースへ","authors":"令 小川","doi":"10.1272/manms.19.247","DOIUrl":"https://doi.org/10.1272/manms.19.247","url":null,"abstract":"","PeriodicalId":35560,"journal":{"name":"Journal of Tokyo Medical University","volume":"15 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-08-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"135989969","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Chronic expanding hematomas (CEH) are hematomas that continue to expand at least one month after onset. CEH often occur in the thoracic cavity or in the extremities secondary to trauma, surgery, anticoagulation therapy, or bleeding disorders. Few studies have reported CEH in retroperitoneal organs such as the adrenal glands and lesions without an apparent etiology. An 80-year-old woman was referred to our hospital for evaluation of a retroperitoneal tumor that was incidentally detected on ultrasonography. Computed tomography and magnetic resonance imaging showed a large left retroperitoneal mass (14 cm in diameter) with gradual peripheral enhancement and a suspected hemorrhagic component within the lesion. Parametric imaging using positron emission tomography (PET) showed mild accumulation of the tracer at the margins of the mass on the conventional standard uptake value images, relatively low accumulation on the slope images, and slightly higher accumulation on intercept images. Postoperative histopathological examination of the resected specimen revealed a mass that was encapsulated with fibrous tissue and primarily consisted of organized clots without evidence of tumor cells; the mass was diagnosed as an idiopathic CEH of the adrenal glands. The margins of the mass showed few inflammatory cell infiltrates consistent with the findings of parametric imaging, which appeared to accurately reflect the dynamics of fluorodeoxyglucose (FDG) in the body. PET parametric imaging can separately assess the metabolism and distribution of FDG in vivo and may be useful to determine the etiology and diagnosis of CEH.
{"title":"PETパラメトリックイメージングが診断の一助となった副腎のchronic expanding hematomaの1例","authors":"Nobuhiko Hayashi, Tomonari Kiriyama, Rika Kobayashi, Teppei Nakagomi, Nahiro Yan, Shin-ichiro Kumita, Go Kimura, Yukihiro Kondo","doi":"10.1272/manms.19.263","DOIUrl":"https://doi.org/10.1272/manms.19.263","url":null,"abstract":"Chronic expanding hematomas (CEH) are hematomas that continue to expand at least one month after onset. CEH often occur in the thoracic cavity or in the extremities secondary to trauma, surgery, anticoagulation therapy, or bleeding disorders. Few studies have reported CEH in retroperitoneal organs such as the adrenal glands and lesions without an apparent etiology. An 80-year-old woman was referred to our hospital for evaluation of a retroperitoneal tumor that was incidentally detected on ultrasonography. Computed tomography and magnetic resonance imaging showed a large left retroperitoneal mass (14 cm in diameter) with gradual peripheral enhancement and a suspected hemorrhagic component within the lesion. Parametric imaging using positron emission tomography (PET) showed mild accumulation of the tracer at the margins of the mass on the conventional standard uptake value images, relatively low accumulation on the slope images, and slightly higher accumulation on intercept images. Postoperative histopathological examination of the resected specimen revealed a mass that was encapsulated with fibrous tissue and primarily consisted of organized clots without evidence of tumor cells; the mass was diagnosed as an idiopathic CEH of the adrenal glands. The margins of the mass showed few inflammatory cell infiltrates consistent with the findings of parametric imaging, which appeared to accurately reflect the dynamics of fluorodeoxyglucose (FDG) in the body. PET parametric imaging can separately assess the metabolism and distribution of FDG in vivo and may be useful to determine the etiology and diagnosis of CEH.","PeriodicalId":35560,"journal":{"name":"Journal of Tokyo Medical University","volume":"9 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-08-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"135989967","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
In recent years, gene and cell therapies have become widely accepted as new therapeutic modalities, and a number of gene therapy drugs have been approved. Underlying this advance are innovations in gene delivery tools, especially viral vectors, which are no longer simply gene transfer tools in basic research. Since its initial inception, all aspects of gene therapy have been dramatically improved, including their safety, functionality, and production technology. On the other hand, with use of gene therapies clinically, new safety and efficacy concerns have emerged, and gene therapy is now entering a new phase. Both preclinical and clinical data have demonstrated that simple overexpression of a therapeutic gene at a disease site through transduction by a gene delivery vector is not sufficient to ensure safety and therapeutic efficacy. Maturation of this field will require more sophisticated gene delivery vector systems and highly regulated therapeutic gene expression systems to precisely introduce these genes into target cells and express them to the appropriate degree at the appropriate time. Herpes simplex virus (HSV)-based vectors are extremely safe and functional vector systems that have the potential to meet current challenges in gene and cell therapy. This makes HSV vectors promising gene delivery vehicles for gene therapy. This chapter will focus on the current trends in the development of HSV as a delivery vector for gene therapy.
{"title":"Development of Herpes Simplex Virus-based Vectors for Gene Therapy","authors":"Yoshitaka Miyagawa","doi":"10.1272/manms.19.218","DOIUrl":"https://doi.org/10.1272/manms.19.218","url":null,"abstract":"In recent years, gene and cell therapies have become widely accepted as new therapeutic modalities, and a number of gene therapy drugs have been approved. Underlying this advance are innovations in gene delivery tools, especially viral vectors, which are no longer simply gene transfer tools in basic research. Since its initial inception, all aspects of gene therapy have been dramatically improved, including their safety, functionality, and production technology. On the other hand, with use of gene therapies clinically, new safety and efficacy concerns have emerged, and gene therapy is now entering a new phase. Both preclinical and clinical data have demonstrated that simple overexpression of a therapeutic gene at a disease site through transduction by a gene delivery vector is not sufficient to ensure safety and therapeutic efficacy. Maturation of this field will require more sophisticated gene delivery vector systems and highly regulated therapeutic gene expression systems to precisely introduce these genes into target cells and express them to the appropriate degree at the appropriate time. Herpes simplex virus (HSV)-based vectors are extremely safe and functional vector systems that have the potential to meet current challenges in gene and cell therapy. This makes HSV vectors promising gene delivery vehicles for gene therapy. This chapter will focus on the current trends in the development of HSV as a delivery vector for gene therapy.","PeriodicalId":35560,"journal":{"name":"Journal of Tokyo Medical University","volume":"104 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-08-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"135989962","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Lysosomal storage diseases (LSDs) are a heterogeneous group of diseases caused by genetically determined defects in lysosomal enzymes. Specific molecular mechanisms and disease phenotypes depend on the type of storage material affected. Current treatments for LSDs include enzyme replacement therapy (ERT) and hematopoietic cell transplantation (HCT) from allogeneic healthy individuals. However, those approaches are applicable only to a limited number of LSDs and lack efficacy for some clinical conditions. Hematopoietic stem cell gene therapy (HSC-GT) incorporating lentiviral vectors has shown strong clinical efficacy when administered to patients with metachromatic leukodystrophy (MLD) and is now registered as a pharmaceutical product. More recently, HSC-GT has also shown promising results in patients with Hurler’s syndrome. Here, we report on the treatment for MLD currently being used in clinical practice and the gene therapy for MLD being studied at Nippon Medical School.
{"title":"Gene Therapy for Metachromatic Leukodystrophy; MLD","authors":"Noriko Miyake","doi":"10.1272/manms.19.224","DOIUrl":"https://doi.org/10.1272/manms.19.224","url":null,"abstract":"Lysosomal storage diseases (LSDs) are a heterogeneous group of diseases caused by genetically determined defects in lysosomal enzymes. Specific molecular mechanisms and disease phenotypes depend on the type of storage material affected. Current treatments for LSDs include enzyme replacement therapy (ERT) and hematopoietic cell transplantation (HCT) from allogeneic healthy individuals. However, those approaches are applicable only to a limited number of LSDs and lack efficacy for some clinical conditions. Hematopoietic stem cell gene therapy (HSC-GT) incorporating lentiviral vectors has shown strong clinical efficacy when administered to patients with metachromatic leukodystrophy (MLD) and is now registered as a pharmaceutical product. More recently, HSC-GT has also shown promising results in patients with Hurler’s syndrome. Here, we report on the treatment for MLD currently being used in clinical practice and the gene therapy for MLD being studied at Nippon Medical School.","PeriodicalId":35560,"journal":{"name":"Journal of Tokyo Medical University","volume":"82 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-08-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"135989974","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"悪性黒色腫の薬物治療と問題点","authors":"俊彦 帆足","doi":"10.1272/manms.19.269","DOIUrl":"https://doi.org/10.1272/manms.19.269","url":null,"abstract":"","PeriodicalId":35560,"journal":{"name":"Journal of Tokyo Medical University","volume":"10 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-08-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"135989971","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Hypophosphatasia (HPP) is an inherited bone disease resulting from a deficiency of tissue-nonspecific alkaline phosphatase (TNALP). It is fatal in its severe perinatal and infantile forms. Asfotase alfa (Strensiq®) is an approved enzyme replacement therapy for HPP. It's use requires injections 3-6 times per week for all of the patient's life. Therefore, although this treatment is effective, it is also burdensome. We investigated the efficacy and safety of a gene therapy drug (TNALP-D10-expressing type 8 adeno-associated virus vector: ARU-2801) administered intramuscularly to Alpl−/− mice (infantile HPP model) and non-human primates with the aim of developing a less burdensome treatment. After administration of 3.0×1011 vg/body (n=4/7) or 1.0×1012 vg/body (n=5/7) ARU-2801, treated mice maintained high plasma ALP activity and exhibited body weight gain and bone maturity similar to wild-type mice throughout their survival period, which was up to 18 months. Biodistribution of ARU-2801 was detected only in the intramuscular region on the administration side. There were no tumors or ectopic calcification detected at autopsy or histopathological examination. After administration of 1.0×1013 vg/body ARU-2801 to juvenile macaque monkeys, durable high plasma ALP levels were sustained for up to 38 weeks with no biochemical abnormalities detected in the blood. Radiological and histopathological examinations also showed no abnormality. The clinical chemistry parameters for ARU-2801-treated mice and macaques indicated that plasma ALP activity is maintained with no toxicities at levels that are potentially clinically efficacious. Thus, ARU-2801, which can be administered as a single dose, has the potential to improve the quality of life of HPP patients by eliminating the need for indefinitely repeated injections.
{"title":"Gene Therapy for Hypophosphatasia in <i>Alpl</i><sup>−/−</sup> mice (infantile HPP model) -Toward Clinical Application","authors":"Tae Matsumoto","doi":"10.1272/manms.19.229","DOIUrl":"https://doi.org/10.1272/manms.19.229","url":null,"abstract":"Hypophosphatasia (HPP) is an inherited bone disease resulting from a deficiency of tissue-nonspecific alkaline phosphatase (TNALP). It is fatal in its severe perinatal and infantile forms. Asfotase alfa (Strensiq®) is an approved enzyme replacement therapy for HPP. It's use requires injections 3-6 times per week for all of the patient's life. Therefore, although this treatment is effective, it is also burdensome. We investigated the efficacy and safety of a gene therapy drug (TNALP-D10-expressing type 8 adeno-associated virus vector: ARU-2801) administered intramuscularly to Alpl−/− mice (infantile HPP model) and non-human primates with the aim of developing a less burdensome treatment. After administration of 3.0×1011 vg/body (n=4/7) or 1.0×1012 vg/body (n=5/7) ARU-2801, treated mice maintained high plasma ALP activity and exhibited body weight gain and bone maturity similar to wild-type mice throughout their survival period, which was up to 18 months. Biodistribution of ARU-2801 was detected only in the intramuscular region on the administration side. There were no tumors or ectopic calcification detected at autopsy or histopathological examination. After administration of 1.0×1013 vg/body ARU-2801 to juvenile macaque monkeys, durable high plasma ALP levels were sustained for up to 38 weeks with no biochemical abnormalities detected in the blood. Radiological and histopathological examinations also showed no abnormality. The clinical chemistry parameters for ARU-2801-treated mice and macaques indicated that plasma ALP activity is maintained with no toxicities at levels that are potentially clinically efficacious. Thus, ARU-2801, which can be administered as a single dose, has the potential to improve the quality of life of HPP patients by eliminating the need for indefinitely repeated injections.","PeriodicalId":35560,"journal":{"name":"Journal of Tokyo Medical University","volume":"22 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-08-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"135989975","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
A quarter of a century has passed since the expected realization of "Conquering cancer in the 21st century" due to advances in pharmaceuticals and medical technology. However, the effectiveness of treatments for malignant tumors, especially refractory cancers, remains inadequate and is difficult to achieve with conventional treatment methods alone. For example, there are high rates of metastasis and residual recurrence following surgical treatment, while chemotherapy and radiotherapy all too quickly lead to disease resistance, and their side effects significantly reduce patients’ quality of life. Under such circumstances, gene therapy products targeting cancer are some of the most highly desired therapies worldwide. The advantages of these innovative treatments are their clear mechanism of action and clinical efficacy based on molecular pathology. Several gene therapies have been approved for hematologic tumors and have shown dramatic therapeutic effects. On the other hand, the efficacy of gene therapies against solid tumors remains limited and improving their therapeutic efficacy remains a major challenge. In this review, we report the background and current status of gene therapy for cancer. In addition, oncolytic virus therapy and CAR-T cell therapy, which have the potential to be curative and are undergoing research and development, will be introduced in detail.
{"title":"Gene Therapy for Cancer","authors":"Seiji Kuroda, Makoto Sukegawa","doi":"10.1272/manms.19.235","DOIUrl":"https://doi.org/10.1272/manms.19.235","url":null,"abstract":"A quarter of a century has passed since the expected realization of \"Conquering cancer in the 21st century\" due to advances in pharmaceuticals and medical technology. However, the effectiveness of treatments for malignant tumors, especially refractory cancers, remains inadequate and is difficult to achieve with conventional treatment methods alone. For example, there are high rates of metastasis and residual recurrence following surgical treatment, while chemotherapy and radiotherapy all too quickly lead to disease resistance, and their side effects significantly reduce patients’ quality of life. Under such circumstances, gene therapy products targeting cancer are some of the most highly desired therapies worldwide. The advantages of these innovative treatments are their clear mechanism of action and clinical efficacy based on molecular pathology. Several gene therapies have been approved for hematologic tumors and have shown dramatic therapeutic effects. On the other hand, the efficacy of gene therapies against solid tumors remains limited and improving their therapeutic efficacy remains a major challenge. In this review, we report the background and current status of gene therapy for cancer. In addition, oncolytic virus therapy and CAR-T cell therapy, which have the potential to be curative and are undergoing research and development, will be introduced in detail.","PeriodicalId":35560,"journal":{"name":"Journal of Tokyo Medical University","volume":"7 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-08-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"135989964","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
In the field of ophthalmology, gene therapy has focused on hereditary retinal dystrophy, including retinitis pigmentosa. Hereditary retinal dystrophy is a group of intractable diseases for which there is currently no effective treatment, and expectations are focused on gene therapy and retinal regeneration therapy using iPS cells. In recent years, results of a number of clinical trials of gene therapies for hereditary retinal dystrophy have been reported from Europe and the United States. Since 2017, gene therapy drugs for Leber congenital amaurosis have been approved after being found to be safe and therapeutically efficacious. In this article, we will discuss the current state of gene therapy for retinitis pigmentosa and the use of adeno-associated virus (AAV) vectors in gene therapy.
{"title":"Gene Therapy for Ophthalmic Diseases","authors":"Tsutomu Igarashi","doi":"10.1272/manms.19.242","DOIUrl":"https://doi.org/10.1272/manms.19.242","url":null,"abstract":"In the field of ophthalmology, gene therapy has focused on hereditary retinal dystrophy, including retinitis pigmentosa. Hereditary retinal dystrophy is a group of intractable diseases for which there is currently no effective treatment, and expectations are focused on gene therapy and retinal regeneration therapy using iPS cells. In recent years, results of a number of clinical trials of gene therapies for hereditary retinal dystrophy have been reported from Europe and the United States. Since 2017, gene therapy drugs for Leber congenital amaurosis have been approved after being found to be safe and therapeutically efficacious. In this article, we will discuss the current state of gene therapy for retinitis pigmentosa and the use of adeno-associated virus (AAV) vectors in gene therapy.","PeriodicalId":35560,"journal":{"name":"Journal of Tokyo Medical University","volume":"1 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-08-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"135989978","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Gastric cancer used to be the leading cause of cancer mortality in Japan, but the rate has been decreasing in recent years due to declining numbers of Helicobacter pylori infections. However, even now, it is still a major cancer in this country, ranking third in both the number of cases (2019) and number of deaths (2020). Treatment in the preoperative stages has improved thanks to the increased accuracy of preoperative examinations such as endoscopy and computed tomography, with treatment decisions based on prognosis in consideration of the stage of the disease, and the degree of invasiveness the patient will be able to tolerate. Endoscopic resection is indicated for mucosal cancer without lymph node metastasis (stage IA), while anticancer agents are used for stage IV patients with peritoneal dissemination and other cases where radical resection is impossible. Otherwise, surgery is the main treatment. In the past, open surgery dominated, but in recent years, minimally invasive laparoscopic surgery that creates smaller wounds has become widespread. Recently, robotic surgery with such functions as camera shake prevention has been developed, and this enables even more precise surgery. With reference to our own research, this article outlines the historical evolution of gastric cancer surgery and the current status of minimally invasive surgery.
{"title":"わが国における胃癌に対する低侵襲手術の現況","authors":"Nobuyuki Sakurazawa","doi":"10.1272/manms.19.254","DOIUrl":"https://doi.org/10.1272/manms.19.254","url":null,"abstract":"Gastric cancer used to be the leading cause of cancer mortality in Japan, but the rate has been decreasing in recent years due to declining numbers of Helicobacter pylori infections. However, even now, it is still a major cancer in this country, ranking third in both the number of cases (2019) and number of deaths (2020). Treatment in the preoperative stages has improved thanks to the increased accuracy of preoperative examinations such as endoscopy and computed tomography, with treatment decisions based on prognosis in consideration of the stage of the disease, and the degree of invasiveness the patient will be able to tolerate. Endoscopic resection is indicated for mucosal cancer without lymph node metastasis (stage IA), while anticancer agents are used for stage IV patients with peritoneal dissemination and other cases where radical resection is impossible. Otherwise, surgery is the main treatment. In the past, open surgery dominated, but in recent years, minimally invasive laparoscopic surgery that creates smaller wounds has become widespread. Recently, robotic surgery with such functions as camera shake prevention has been developed, and this enables even more precise surgery. With reference to our own research, this article outlines the historical evolution of gastric cancer surgery and the current status of minimally invasive surgery.","PeriodicalId":35560,"journal":{"name":"Journal of Tokyo Medical University","volume":"382 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-08-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"135989968","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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