Arkhiv patologii最新文献

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Review of the textbook «Pathological anatomy» edited by V.S. Paukov M.: GEOTAR-Media; 2022;752 复习教科书«病理解剖»由V.S. Paukov M.编辑:GEOTAR-Media;2022年,752年
Arkhiv patologii Pub Date : 2023-01-01 DOI: 10.17116/patol20238501179
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引用次数: 0
[Relationship between PD-L1 expression and tumor stem cell marker CD44 as a promising basis for the development of new approaches to cancer targeted therapy]. [PD-L1表达与肿瘤干细胞标志物CD44的关系为开发癌症靶向治疗新方法提供了有希望的基础]。
Arkhiv patologii Pub Date : 2023-01-01 DOI: 10.17116/patol20238506170
T N Sotnikova, T V Polushkina, N V Danilova
{"title":"[Relationship between PD-L1 expression and tumor stem cell marker CD44 as a promising basis for the development of new approaches to cancer targeted therapy].","authors":"T N Sotnikova, T V Polushkina, N V Danilova","doi":"10.17116/patol20238506170","DOIUrl":"10.17116/patol20238506170","url":null,"abstract":"<p><p>Immunotherapy of malignant tumors is a rapidly developing area of oncology. PD-1 is a receptor expressed by activated T-lymphocytes. As a result of its interaction with the ligand (PD-L1 or PD-L2), the activity of T-lymphocytes is inhibited and their apoptosis occurs. Drugs that inhibit the interaction of PD-1 with ligands have an immunostimulatory effect and are effective in the treatment of many types of neoplasms: melanoma, lung cancer, bladder cancer, stomach cancer, various lymphomas, etc. However, response to this treatment is observed only in a narrow cohort of patients. To increase the effectiveness of immunotherapy, combined preparations and nanoparticles are being developed and created to enhance the effect of PD-L1 inhibitors, and containing hyaluronic acid as a ligand for the CD44 protein, which is expressed in many human tumors. However, the issue of co-expression of CD44 and PD-L1 remains poorly understood. This review is devoted to describing the features of co-expression and the mechanisms of interaction between CD44 and PD-L1. Promising directions for the development of new approaches to the immunotherapy of malignant tumors are presented.</p>","PeriodicalId":8548,"journal":{"name":"Arkhiv patologii","volume":"85 6","pages":"70-75"},"PeriodicalIF":0.0,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138443683","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}
引用次数: 0
[E-cadherin: structure and functions, role in gastric cancer carcinogenesis]. e -钙粘蛋白:结构和功能,在胃癌发生中的作用。
Arkhiv patologii Pub Date : 2023-01-01 DOI: 10.17116/patol20238504170
N V Danilova, N A Oleynikova
{"title":"[E-cadherin: structure and functions, role in gastric cancer carcinogenesis].","authors":"N V Danilova,&nbsp;N A Oleynikova","doi":"10.17116/patol20238504170","DOIUrl":"https://doi.org/10.17116/patol20238504170","url":null,"abstract":"<p><p>This review is dedicated to E-cadherin, a calcium-dependent cell-cell adhesion molecule with pivotal roles in epithelial cell behavior, tissue formation, and carcinogenesis. We summarize the structure of the E-cadherin, its role in the development of the body and in the carcinogenesis. The structure of the E-cadherin/β-catenin/αE-catenin complex and its relationship with the actin cytoskeleton are described in detail. The role of E-cadherin in the development of some infectious diseases, the function of E-cadherin as both a tumor suppressor and a promoter of tumor dissemination, its influence on signal transduction pathways in cells are highlighted. Particular attention is paid to the expression of E-cadherin in Helicobacter pylori infection and in tumor tissue in gastric cancer.</p>","PeriodicalId":8548,"journal":{"name":"Arkhiv patologii","volume":"85 4","pages":"70-77"},"PeriodicalIF":0.0,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9926794","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}
引用次数: 0
[Astrocytoma with 1p19q codeletion]. [伴有1p19q编码缺失的星形细胞瘤]。
Arkhiv patologii Pub Date : 2023-01-01 DOI: 10.17116/patol20238501151
M V Ryzhova, S A Galstyan, L V Shishkina, T N Panina, E I Voronina, E N Telysheva, A O Kotelnikova, D V Starovoitov, E G Shaikhaev, G P Snigireva, R V Sycheva, Sh U Kadyrov, A R Adaev, D I Pitskhelauri, E S Kudieva, O G Zheludkova, A V Golanov
{"title":"[Astrocytoma with 1p19q codeletion].","authors":"M V Ryzhova,&nbsp;S A Galstyan,&nbsp;L V Shishkina,&nbsp;T N Panina,&nbsp;E I Voronina,&nbsp;E N Telysheva,&nbsp;A O Kotelnikova,&nbsp;D V Starovoitov,&nbsp;E G Shaikhaev,&nbsp;G P Snigireva,&nbsp;R V Sycheva,&nbsp;Sh U Kadyrov,&nbsp;A R Adaev,&nbsp;D I Pitskhelauri,&nbsp;E S Kudieva,&nbsp;O G Zheludkova,&nbsp;A V Golanov","doi":"10.17116/patol20238501151","DOIUrl":"https://doi.org/10.17116/patol20238501151","url":null,"abstract":"<p><p>Using the example of a recurrent tumor with a 10-year follow-up, the authors show that mutation of the <i>IDH1/2</i> genes in astrocytomas is not always an early event in the pathogenesis of glioma, that in rare cases a 1p19q codeletion can be found in astrocytomas, and that IDH-mutant tumors can occur in childhood.</p>","PeriodicalId":8548,"journal":{"name":"Arkhiv patologii","volume":"85 1","pages":"51-56"},"PeriodicalIF":0.0,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10713057","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}
引用次数: 0
[Glomerulopathy in kidney neoplasms: frequency of occurrence, structure of morbidity]. 【肾脏肿瘤中的肾小球病变:发生频率、发病结构】。
Arkhiv patologii Pub Date : 2023-01-01 DOI: 10.17116/patol20238502121
T A Garkusha, E S Stolyarevich, V A Khorzhevskii, S V Ivliev
{"title":"[Glomerulopathy in kidney neoplasms: frequency of occurrence, structure of morbidity].","authors":"T A Garkusha,&nbsp;E S Stolyarevich,&nbsp;V A Khorzhevskii,&nbsp;S V Ivliev","doi":"10.17116/patol20238502121","DOIUrl":"https://doi.org/10.17116/patol20238502121","url":null,"abstract":"<p><p></p><p><p></p><p><p></p><p><p></p><p><p></p><p><p></p><p><p></p><p><p></p><p><p></p><p><p></p><p><p></p><p><p></p><p><p></p><p><p></p><p><p></p><p><p></p><p><p></p><p><p></p><p><strong>Background: </strong>Malignant neoplasms of the kidneys are among the 10 most common oncological diseases in Russia, in which various kidney lesions can occur, including glomerulopathy. Glomerular pathology can be an independent nosology, a manifestation of paraneoplastic syndrome or metabolic disturbances.</p><p><strong>Objective: </strong>Evaluation of the incidence and structure of glomerulopathies in patients with kidney neoplasms.</p><p><strong>Material and methods: </strong>We analyzed 141 samples with a tumor obtained during nephrectomy. To diagnose glomerular pathology, a fragment of the kidney parenchyma was examined at a distance of at least 4 cm from the tumor border. Histological slides were stained with hematoxylin and eosin, methenamine silver, trichrome Masson, Congo red, PAS reaction was performed. Immunofluorescent microscopy was performed with antibodies to IgA, IgG, IgM, C3c, C1q, Kappa light chain and Lambda light chain. Samples for electron microscopy were contrasted with a solution of 0.1% lead citrate.</p><p><strong>Results: </strong>Malignant neoplasms were diagnosed in 130 (92.2%) patients, benign ones - in 11 (7.8%) patients. In 59 patients with kidney tumors, glomerulopathies were detected, which amounted to 41.8%. All cases of glomerulopathies were diagnosed in combination with carcinomas of the kidneys and renal pelvis. Among 59 cases of glomerulopathy, diabetic nephropathy was diagnosed in 44 (74.6%) cases, IgA nephropathy - in 7 (11.9%) cases, membranous nephropathy - in 1 (1.6%), minimal change disease - in 2 (3.4%), focal segmental glomerulosclerosis - in 5 (8.5%).</p><p><strong>Conclusion: </strong>The study demonstrates a high incidence of glomerulopathies in patients with malignant kidney tumors. The performed work emphasizes the importance of an in-depth morphological study of the kidneys in the presence of a tumor with an integrated approach to the treatment of patients.</p>","PeriodicalId":8548,"journal":{"name":"Arkhiv patologii","volume":"85 2","pages":"21-26"},"PeriodicalIF":0.0,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9664911","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}
引用次数: 0
[Predictive markers of immunotherapy in cervical cancer]. [宫颈癌症免疫疗法的预测标志物]。
Arkhiv patologii Pub Date : 2023-01-01 DOI: 10.17116/patol2023850515
E M Oliushina, L E Zavalishina, Yu Yu Andreeva, O A Kuznetsova, L V Moskvina, G A Frank
{"title":"[Predictive markers of immunotherapy in cervical cancer].","authors":"E M Oliushina,&nbsp;L E Zavalishina,&nbsp;Yu Yu Andreeva,&nbsp;O A Kuznetsova,&nbsp;L V Moskvina,&nbsp;G A Frank","doi":"10.17116/patol2023850515","DOIUrl":"10.17116/patol2023850515","url":null,"abstract":"<p><strong>Objective: </strong>Study of PD-L1 expression in squamous and adenosquamous cell cervical cancer (CC) by immunohistochemical (IHC) method, assessment of the relationship between PD-L1 tumor status and its clinical and morphological characteristics, TILs, MSI/dMMR, and HPV tumor status.</p><p><strong>Material and methods: </strong>Surgical material was obtained from 41 patients with CC, on which the expression of PD-L1, proteins of the MMR system and p16 was studied by the IHC method, the TILs index was determined.</p><p><strong>Results: </strong>Positive PD-L1 status was found in 51.2% of the studied CC samples. In the study sample, the level of PD-L1 expression depended on the severity of lymphoid infiltration of the tumor (<i>p</i>=0.038), it was shown that a positive PD-L1 status of CC can be expected with a TILs value greater than or equal to 50%. The age of the patients, the histological variant of the tumor, the pT and pN stage, the presence of lymphovascular invasion, and the HPV status did not statistically significantly affect the level of PD-L1 expression, however, there was an association between the PD-L1 status and the grade of CC malignancy (<i>p</i>=0.027). The presence of the MSI/dMMR phenomenon was detected in a small percentage of carcinomas (4.9%), the PD-L1 status of these tumors was determined as positive.</p><p><strong>Conclusion: </strong>A positive PD-L1 status is determined in a significant number of cases of CC, regardless of most of the studied clinical and morphological characteristics; there is a statistically significant relationship between PD-L1 expression and the degree of tumor differentiation and TILs. It has been shown that CC with the MSI/dMMR phenomenon is characterized by a positive PD-L1 status. The authors consider it necessary to study the expression of PD-L1 in patients with cervical carcinomas in order to determine the possibility of prescribing personalized therapy with immune checkpoint inhibitors.</p>","PeriodicalId":8548,"journal":{"name":"Arkhiv patologii","volume":"85 5","pages":"5-12"},"PeriodicalIF":0.0,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41181932","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}
引用次数: 0
In Memory of Professor Antonina Sergeevna Gordeladze 纪念安东尼娜·谢尔盖耶夫娜·戈德拉泽教授
Arkhiv patologii Pub Date : 2023-01-01 DOI: 10.17116/patol20238501180
{"title":"In Memory of Professor Antonina Sergeevna Gordeladze","authors":"","doi":"10.17116/patol20238501180","DOIUrl":"https://doi.org/10.17116/patol20238501180","url":null,"abstract":"","PeriodicalId":8548,"journal":{"name":"Arkhiv patologii","volume":"1 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"67406727","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}
引用次数: 0
[Transcriptome analysis of tissue microbiota diversity in tumor and non-tumor lymph nodes]. [肿瘤和非肿瘤淋巴结组织微生物多样性的转录组分析]。
Arkhiv patologii Pub Date : 2023-01-01 DOI: 10.17116/patol20238506126
N S Gladyshev, D V Baram, A V Gorbunova, Yu A Krivolapov
{"title":"[Transcriptome analysis of tissue microbiota diversity in tumor and non-tumor lymph nodes].","authors":"N S Gladyshev, D V Baram, A V Gorbunova, Yu A Krivolapov","doi":"10.17116/patol20238506126","DOIUrl":"10.17116/patol20238506126","url":null,"abstract":"<p><strong>Background: </strong>Metagenomic studies in recent years have demonstrated that all tissues of the human body studied by genomic and transcriptomic sequencing methods, both in pathological processes and in normality, contain fragments of DNA and RNA from a variety of microorganisms. The composition of tissue microbiota and its relationship with development of pathological changes are still poorly understood, despite increasing number of studies in this area every year. In this study, gene expression of the lymph node microbiome in reactive follicular hyperplasia and follicular lymphoma was investigated.</p><p><strong>Objective: </strong>To study expression of lymph node microbiome genes in reactive follicular hyperplasia and follicular lymphoma.</p><p><strong>Material and methods: </strong>The work included 38 biopsy samples of lymph nodes with follicular lymphoma of different cytological subtypes and 10 biopsy samples of lymph nodes with reactive follicular hyperplasia. Verification of diagnosis was carried out using standard histological, histochemical and immunohistochemical methods. Using sequencing method, the transcriptome was examined. Statistical analysis and data visualization were performed using the R programming language (version 4.2.1).</p><p><strong>Results: </strong>Tumor lymph nodes are characterized by large Simpson and Shannon alpha diversity values (p-value = 0.026465 and p-value = 0.007122, respectively). Two clusters were discovered, characterized by different levels of relative abundance of microorganisms.</p><p><strong>Conclusion: </strong>It has been proven that diversity of microorganisms present in tumor tissue and their number are statistically significantly higher than corresponding indicators in the lymph nodes with follicular hyperplasia.</p>","PeriodicalId":8548,"journal":{"name":"Arkhiv patologii","volume":"85 6","pages":"26-30"},"PeriodicalIF":0.0,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138443687","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}
引用次数: 0
[Investigation of the mutational status of the FGFR3 gene in urothelial bladder carcinoma]. [FGFR3基因在尿路上皮性膀胱癌中突变状态的研究]。
Arkhiv patologii Pub Date : 2023-01-01 DOI: 10.17116/patol2023850215
E M Oliushina, L E Zavalishina, E Yu Alekseenok, N A Oskina, Yu Yu Andreeva, O A Kuznetsova, M L Filipenko, G A Frank
{"title":"[Investigation of the mutational status of the FGFR3 gene in urothelial bladder carcinoma].","authors":"E M Oliushina,&nbsp;L E Zavalishina,&nbsp;E Yu Alekseenok,&nbsp;N A Oskina,&nbsp;Yu Yu Andreeva,&nbsp;O A Kuznetsova,&nbsp;M L Filipenko,&nbsp;G A Frank","doi":"10.17116/patol2023850215","DOIUrl":"https://doi.org/10.17116/patol2023850215","url":null,"abstract":"<p><strong>Objective: </strong>To study the somatic mutational status of the <i>FGFR3</i> gene in urothelial bladder cancer (BC) and evaluate its relationship with the clinical and morphological characteristics of the tumor, deficiency of the DNA mismatch repair (dMMR), PD-L1 tumor status, and immunohistochemical (IHC) expression of the p16 protein.</p><p><strong>Material and methods: </strong>Surgical material of 40 patients with BC, on which the mutational status of the <i>FGFR3</i> gene was studied using the molecular genetic method, as well as the MMR status, PD-L1 and p16 expression by the IHC method.</p><p><strong>Results: </strong><i>FGFR3</i> mutations, such as G370C, S249C, S371C/Y373C, R248C, were detected in 35.0% of the studied BC samples. FGFR3 status did not depend on the gender and age of patients, as well as on the degree of tumor lymphoid infiltration (TILs). Statistically significant differences were found in the analysis of FGFR3 status depending on the histological structure and degree of tumor differentiation, as well as on the pT stage. The FGFR3 status of BC was not associated with the IHC expression of the studied proteins of the MMR system, as well as with the PD-L1 status. Higher levels of PD-L1 expression were demonstrated by BC tumor cells, in which no aberrations in <i>FGFR3</i> were detected. There was no significant association between p16 status and the presence of <i>FGFR3</i> mutations, but for FGFR3-positive carcinomas, the basal pattern of p16 staining by IHC was noted.</p><p><strong>Conclusion: </strong>A positive somatic mutational status of the <i>FGFR3</i> gene was statistically significantly more common in the group of papillary low-grade non-muscle-invasive BC, demonstrating basal p16 IHC staining. In the study sample, there was no statistically significant relationship between the FGFR3 status of BC and gender and age differences, TILs, MMR status, PD-L1 status (SP142 and 22C3), and p16 status. The results of the study indicate the need to determine the FGFR3 status in patients with BC for further prescription of personalized therapy.</p>","PeriodicalId":8548,"journal":{"name":"Arkhiv patologii","volume":"85 2","pages":"5-12"},"PeriodicalIF":0.0,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9664909","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}
引用次数: 1
[Evaluation of morphological activity of primary Sjogren's syndrome on bioptates of minor salivary glands]. [原发性干燥综合征对小唾液腺生物酸盐形态学活性的评价]。
Arkhiv patologii Pub Date : 2023-01-01 DOI: 10.17116/patol2023850115
S G Radenska-Lopovok, M S Karanova, A S Zanozin, E B Rodionova, S G Palshina, M S Tsvetanov, A V Tregubova, V I Vasilev
{"title":"[Evaluation of morphological activity of primary Sjogren's syndrome on bioptates of minor salivary glands].","authors":"S G Radenska-Lopovok,&nbsp;M S Karanova,&nbsp;A S Zanozin,&nbsp;E B Rodionova,&nbsp;S G Palshina,&nbsp;M S Tsvetanov,&nbsp;A V Tregubova,&nbsp;V I Vasilev","doi":"10.17116/patol2023850115","DOIUrl":"https://doi.org/10.17116/patol2023850115","url":null,"abstract":"<p><strong>Background: </strong>The results of the morphological study of the minor salivary glands can be used to assess the activity of the primary Sjogren's syndrome and to decide on adequate therapy.The existing protocol of The Sjögren's International Clinical Collaborative Alliance (SICCA) prescribes the methodology for examining biopsy specimens for suspected Sjögren's disease, however, experts interpret data from the analysis of histological preparations differently.</p><p><strong>Objective: </strong>To identify morphological forms of sialadenitis, as well as to determine the focus score in Russian patients based on the retrospective analysis of minor salivary glands biopsies of patients with primary Sjogren's syndrome.</p><p><strong>Material and methods: </strong>Biopsies of minor salivary glands were studied in 92 patients with primary Sjogren's syndrome and 42 patients without rheumatic disease.</p><p><strong>Results: </strong>Focal lymphocytic sialadenitis was detected in 69 patients with primary Sjogren's syndrome. The focus score in patients with primary Sjogren's syndrome was 7.32 (2.8-14.17). In patients without rheumatic diseases, this index was 0.48 (<i>p</i><0.05). Patients with confluent lymphocytic foci need immunohistochemical examination and dynamic monitoring to exclude lymphoproliferative diseases.</p><p><strong>Conclusion: </strong>The index of morphological activity of sialadenitis in primary Sjogren's syndrome ranges from 2.8 to 14.17 and reflects the activity of the underlying disease.It should be taken into account in the diagnosis and prescription of adequate therapy. Further study of the correlations of morphological and clinical and laboratory parameters will lead to clarification of the criterion signs of the disease.</p>","PeriodicalId":8548,"journal":{"name":"Arkhiv patologii","volume":"85 1","pages":"5-9"},"PeriodicalIF":0.0,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10721785","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}
引用次数: 0
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