Cellular and Molecular Gastroenterology and Hepatology最新文献

{"title":"MCPIP1 Inhibits Hepatic Stellate Cell Activation in Autocrine and Paracrine Manners, Preventing Liver Fibrosis","authors":"Natalia Pydyn ,&nbsp;Anna Ferenc ,&nbsp;Katarzyna Trzos ,&nbsp;Ewelina Pospiech ,&nbsp;Mateusz Wilamowski ,&nbsp;Olga Mucha ,&nbsp;Piotr Major ,&nbsp;Justyna Kadluczka ,&nbsp;Pedro M. Rodrigues ,&nbsp;Jesus M. Banales ,&nbsp;Jose M. Herranz ,&nbsp;Matias A. Avila ,&nbsp;Tomasz Hutsch ,&nbsp;Piotr Malczak ,&nbsp;Dorota Radkowiak ,&nbsp;Andrzej Budzynski ,&nbsp;Jolanta Jura ,&nbsp;Jerzy Kotlinowski","doi":"10.1016/j.jcmgh.2024.01.021","DOIUrl":"10.1016/j.jcmgh.2024.01.021","url":null,"abstract":"<div><h3>Background &amp; Aims</h3><p>Hepatic fibrosis is characterized by enhanced deposition of extracellular matrix (ECM), which results from the wound healing response to chronic, repeated injury of any etiology. Upon injury, hepatic stellate cells (HSCs) activate and secrete ECM proteins, forming scar tissue, which leads to liver dysfunction. Monocyte-chemoattractant protein-induced protein 1 (MCPIP1) possesses anti-inflammatory activity, and its overexpression reduces liver injury in septic mice. In addition, mice with liver-specific deletion of <em>Zc3h12a</em> develop features of primary biliary cholangitis. In this study, we investigated the role of MCPIP1 in liver fibrosis and HSC activation.</p></div><div><h3>Methods</h3><p>We analyzed MCPIP1 levels in patients’ fibrotic livers and hepatic cells isolated from fibrotic murine livers. In vitro experiments were conducted on primary HSCs, cholangiocytes, hepatocytes, and LX-2 cells with MCPIP1 overexpression or silencing.</p></div><div><h3>Results</h3><p>MCPIP1 levels are induced in patients’ fibrotic livers compared with their nonfibrotic counterparts. Murine models of fibrosis revealed that its level is increased in HSCs and hepatocytes. Moreover, hepatocytes with Mcpip1 deletion trigger HSC activation via the release of connective tissue growth factor. Overexpression of MCPIP1 in LX-2 cells inhibits their activation through the regulation of <em>TGFB1</em> expression, and this phenotype is reversed upon MCPIP1 silencing.</p></div><div><h3>Conclusions</h3><p>We demonstrated that MCPIP1 is induced in human fibrotic livers and regulates the activation of HSCs in both autocrine and paracrine manners. Our results indicate that MCPIP1 could have a potential role in the development of liver fibrosis.</p></div>","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":null,"pages":null},"PeriodicalIF":7.2,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2352345X24000249/pdfft?md5=1f05034f538c34bcde2cb870e94dd13b&pid=1-s2.0-S2352345X24000249-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139678118","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"RASSF4 Attenuates Metabolic Dysfunction-Associated Steatotic Liver Disease Progression via Hippo Signaling and Suppresses Hepatocarcinogenesis","authors":"Chaofei Xu ,&nbsp;Ting Fang ,&nbsp;Jingru Qu ,&nbsp;Yahui Miao ,&nbsp;Lei Tian ,&nbsp;Man Zhang ,&nbsp;Hao Zhuang ,&nbsp;Bei Sun ,&nbsp;Liming Chen","doi":"10.1016/j.jcmgh.2024.04.005","DOIUrl":"10.1016/j.jcmgh.2024.04.005","url":null,"abstract":"<div><h3>Background &amp; Aims</h3><p>Metabolic dysfunction-associated steatotic liver disease (MASLD) is a dynamic chronic liver disease closely related to metabolic abnormalities such as diabetes and obesity. MASLD can further progress to metabolic dysfunction-associated steatohepatitis (MASH), fibrosis, cirrhosis, and even hepatocellular carcinoma (HCC). However, the mechanisms underlying the progression of MASLD and further progression to liver fibrosis and liver cancer are unknown.</p></div><div><h3>Methods</h3><p>In this study, we performed transcriptome analysis in livers from mice with MASLD and found suppression of a potential anti-oncogene, RAS association domain protein 4 (RASSF4). RASSF4 expression levels were measured in liver or tumor tissues of patients with MASH or HCC, respectively. We established RASSF4 overexpression and knockout mouse models. The effects of RASSF4 were evaluated by quantitative polymerase chain reaction, Western blotting, histopathological analysis, wound healing assays, Transwell assays, EdU incorporation assays, colony formation assays, sorafenib sensitivity assays, and tumorigenesis assays.</p></div><div><h3>Results</h3><p>RASSF4 was significantly down-regulated in MASH and HCC samples. Using liver-specific RASSF4 knockout mice, we demonstrated that loss of hepatic RASSF4 exacerbated hepatic steatosis and fibrosis. In contrast, RASSF4 overexpression prevented steatosis in MASLD mice. In addition, RASSF4 in hepatocytes suppressed the activation of hepatic stellate cells (HSCs) by reducing transforming growth factor beta secretion. Moreover, we found that RASSF4 is an independent prognostic factor for HCC. Mechanistically, we found that RASSF4 in the liver interacts with MST1 to inhibit YAP nuclear translocation through the Hippo pathway.</p></div><div><h3>Conclusions</h3><p>These findings establish RASSF4 as a therapeutic target for MASLD and HCC.</p></div>","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":null,"pages":null},"PeriodicalIF":7.2,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2352345X24000997/pdfft?md5=fa7dbf4b792b21f73f3e62f1830aa251&pid=1-s2.0-S2352345X24000997-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140873697","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Replication Efficiency of SARS-CoV-2 Omicron Subvariants BA.2.75, BA.5, and XBB.1 in Human Mini-Gut Organoids","authors":"Kei Miyakawa,&nbsp;Masakazu Machida,&nbsp;Tomoyuki Kawasaki,&nbsp;Masatoshi Kakizaki,&nbsp;Yayoi Kimura,&nbsp;Masaya Sugiyama,&nbsp;Hideki Hasegawa,&nbsp;Akihiro Umezawa,&nbsp;Hidenori Akutsu,&nbsp;Akihide Ryo","doi":"10.1016/j.jcmgh.2024.03.003","DOIUrl":"10.1016/j.jcmgh.2024.03.003","url":null,"abstract":"","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":null,"pages":null},"PeriodicalIF":7.2,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2352345X24000559/pdfft?md5=11f8ae8dd4372508c084a3a512815b8d&pid=1-s2.0-S2352345X24000559-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140144712","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Enteroendocrine Cell Loss Drives Small Intestinal Hypomotility in Colitis","authors":"Jacques Gonzales","doi":"10.1016/j.jcmgh.2024.03.012","DOIUrl":"10.1016/j.jcmgh.2024.03.012","url":null,"abstract":"","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":null,"pages":null},"PeriodicalIF":7.2,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2352345X24000675/pdfft?md5=209f8a374b09eda8431f8715551e4b13&pid=1-s2.0-S2352345X24000675-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140767454","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Hepatocyte Deubiquitinating Enzyme OTUD5 Deficiency Is a Key Aggravator for Metabolic Dysfunction-Associated Steatohepatitis by Disturbing Mitochondrial Homeostasis","authors":"Jingjing Dai ,&nbsp;Liren Zhang ,&nbsp;Ruizhi Zhang ,&nbsp;Jing Ge ,&nbsp;Feifan Yao ,&nbsp;Suiqing Zhou ,&nbsp;Jiali Xu ,&nbsp;Kai Yu ,&nbsp;Jing Xu ,&nbsp;Longfeng Jiang ,&nbsp;Ke Jin ,&nbsp;Xinzheng Dai ,&nbsp;Jun Li ,&nbsp;Qing Li","doi":"10.1016/j.jcmgh.2023.11.014","DOIUrl":"10.1016/j.jcmgh.2023.11.014","url":null,"abstract":"<div><h3>Background &amp; Aims</h3><p>Metabolic dysfunction–associated steatohepatitis (MASH) is a common chronic liver disease worldwide. No effective pharmacologic therapies for MASH have been developed; to develop such promising drugs, the underlying mechanisms regulating MASH need to be elucidated. Here, we aimed to determine the role of ovarian tumor domain-containing protein 5 (OTUD5) in MASH progression and identify a specific mechanism.</p></div><div><h3>Methods</h3><p>The expression levels of OTUD subfamily under palmitic acid/oleic acid (PAOA) stimulation were screened. OTUD5 expression was assessed in human liver tissues without steatosis, those with simple steatosis, and those with MASH. MASH models were developed in hepatocyte-specific <em>Otud5</em>-knockout mice that were fed high-fat high-cholesterol and high-fat high-cholesterol plus high-fructose/sucrose diet for 16 weeks.</p></div><div><h3>Results</h3><p>The expression of OTUD5 was down-regulated in fatty liver and was negatively related to the progression of MASH. Lipid accumulation and inflammation were exacerbated by <em>Otud5</em> knockdown but attenuated by <em>Otud5</em> overexpression under PAOA treatment. Hepatocyte-specific <em>Otud5</em> deletion markedly exacerbated steatosis, inflammation, and fibrosis in the livers of 2 MASH mouse models. We identified voltage-dependent anion channel 2 (VDAC2) as an OTUD5-interacting partner; OTUD5 cleaved the K48-linked polyubiquitin chains from VDAC2, and it inhibited subsequent proteasomal degradation. The anabolic effects of OTUD5 knockdown on PAOA-induced lipid accumulation were effectively reversed by VDAC2 overexpression in primary hepatocytes. Metabolomic results revealed that VDAC2 is required for OTUD5-mediated protection against hepatic steatosis by maintaining mitochondrial function.</p></div><div><h3>Conclusions</h3><p>OTUD5 may ameliorate MASH progression via VDAC2-maintained mitochondrial homeostasis. Targeting OTUD5 may be a viable MASH-treatment strategy.</p></div>","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":null,"pages":null},"PeriodicalIF":7.2,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2352345X23002138/pdfft?md5=5c42777cb99d32033c1f7fbc97118eee&pid=1-s2.0-S2352345X23002138-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138464638","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Germline Genetic Associations for Hepatobiliary Cancers","authors":"Perapa Chotiprasidhi ,&nbsp;Angela Karina Sato-Espinoza ,&nbsp;Kirk J. Wangensteen","doi":"10.1016/j.jcmgh.2023.12.010","DOIUrl":"10.1016/j.jcmgh.2023.12.010","url":null,"abstract":"<div><p>Hepatobiliary cancers (HBCs) include hepatocellular carcinoma, cholangiocarcinoma, and gallbladder carcinoma, which originate from the liver, bile ducts, and gallbladder, respectively. They are responsible for a substantial burden of cancer-related deaths worldwide. Despite knowledge of risk factors and advancements in therapeutics and surgical interventions, the prognosis for most patients with HBC remains bleak. There is evidence from familial aggregation and case-control studies to suggest a familial risk component in HBC susceptibility. Recent progress in genomics research has led to the identification of germline variants including single nucleotide polymorphisms (SNPs) and pathogenic or likely pathogenic (P/LP) variants in cancer-associated genes associated with HBC risk. These findings emerged from genome-wide association studies and next-generation sequencing techniques such as whole-exome sequencing. Patients with other cancer types, including breast, colon, ovarian, prostate, and pancreatic cancer, are recommended by guidelines to undergo germline genetic testing, but similar recommendations are lagging in HBC. This prompts the question of whether multi-gene panel testing should be integrated into clinical guidelines for HBC management. Here, we review the hereditary genetics of HBC, explore studies investigating SNPs and P/LP variants in HBC patients, discuss the clinical implications and potential for personalized treatments and impact on patient’s family members, and conclude that additional studies are needed to examine how genetic testing can be applied clinically.</p></div>","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":null,"pages":null},"PeriodicalIF":7.2,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2352345X23002266/pdfft?md5=33fa693822ff52cc04ec5db903d5ea19&pid=1-s2.0-S2352345X23002266-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139065057","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Hepatocellular RECK as a Critical Regulator of Metabolic Dysfunction-associated Steatohepatitis Development","authors":"Ryan J. Dashek ,&nbsp;Rory P. Cunningham ,&nbsp;Christopher L. Taylor ,&nbsp;Isabella Alessi ,&nbsp;Connor Diaz ,&nbsp;Grace M. Meers ,&nbsp;Andrew A. Wheeler ,&nbsp;Jamal A. Ibdah ,&nbsp;Elizabeth J. Parks ,&nbsp;Tadashi Yoshida ,&nbsp;Bysani Chandrasekar ,&nbsp;R. Scott Rector","doi":"10.1016/j.jcmgh.2024.101365","DOIUrl":"10.1016/j.jcmgh.2024.101365","url":null,"abstract":"<div><h3>Background &amp; Aims</h3><p>Reversion-inducing cysteine-rich protein with Kazal motifs (RECK) is an extracellular matrix regulator with anti-fibrotic effects. However, its expression and role in metabolic dysfunction-associated steatohepatitis (MASH) and hepatic fibrosis are poorly understood.</p></div><div><h3>Methods</h3><p>We generated a novel transgenic mouse model with RECK overexpression specifically in hepatocytes to investigate its role in Western diet (WD)-induced liver disease. Proteomic analysis and in vitro studies were performed to mechanistically link RECK to hepatic inflammation and fibrosis.</p></div><div><h3>Results</h3><p>Our results show that RECK expression is significantly decreased in liver biopsies from human patients diagnosed with MASH and correlated negatively with severity of metabolic dysfunction-associated steatotic liver disease (MASLD) and fibrosis. Similarly, RECK expression is downregulated in WD-induced MASH in wild-type mice. Hepatocyte-specific RECK overexpression significantly reduced hepatic pathology in WD-induced liver injury. Proteomic analysis highlighted changes in extracellular matrix and cell-signaling proteins. <em>In vitro</em> mechanistic studies linked RECK induction to reduced ADAM10 (a disintegrin and metalloproteinase domain-containing protein 10) and ADAM17 activity, amphiregulin release, epidermal growth factor receptor activation, and stellate cell activation.</p></div><div><h3>Conclusion</h3><p>Our in vivo and mechanistic in vitro studies reveal that RECK is a novel upstream regulator of inflammation and fibrosis in the diseased liver, its induction is hepatoprotective, and thus highlights its potential as a novel therapeutic in MASH.</p></div>","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":null,"pages":null},"PeriodicalIF":7.1,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2352345X2400119X/pdfft?md5=9bce892f2c6acfc5041f78bf7188f749&pid=1-s2.0-S2352345X2400119X-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141137953","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Oxidized HMGB1 Adducts Unleash Inflammation in Alcohol-Associated Liver Disease","authors":"","doi":"10.1016/j.jcmgh.2024.101375","DOIUrl":"10.1016/j.jcmgh.2024.101375","url":null,"abstract":"","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":null,"pages":null},"PeriodicalIF":7.1,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2352345X24001309/pdfft?md5=1c2cc37f6dab19ca9993ddcd86185655&pid=1-s2.0-S2352345X24001309-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141693355","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Breaking Down the Pain Pathway: Bacterial Proteases Activate Nociceptors to Cause Pain","authors":"","doi":"10.1016/j.jcmgh.2024.03.009","DOIUrl":"10.1016/j.jcmgh.2024.03.009","url":null,"abstract":"","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":null,"pages":null},"PeriodicalIF":7.1,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2352345X24000614/pdfft?md5=648684eeec273507741a68d0e08c1416&pid=1-s2.0-S2352345X24000614-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140782726","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mrgprb2-dependent Mast Cell Activation Plays a Crucial Role in Acute Colitis","authors":"","doi":"10.1016/j.jcmgh.2024.101391","DOIUrl":"10.1016/j.jcmgh.2024.101391","url":null,"abstract":"<div><h3>Background &amp; Aims</h3><div>Mast cells (MCs) are typically found at mucosal surfaces, where their immunoglobulin E (IgE)-dependent activation plays a central role in allergic diseases. Over the past years, signaling through Mas-related G protein-coupled receptor b2 (Mrgprb2) in mice and MRGPRX2 in humans has gained a lot of interest as an alternative MC activation pathway with high therapeutic potential. The aim of this study was to explore the relevance of such IgE-independent, Mrgprb2-mediated signaling in colonic MCs in the healthy and acutely inflamed mouse colon.</div></div><div><h3>Methods</h3><div>Mrgprb2 expression and functionality was studied using a genetic labeling strategy combined with advanced microscopic imaging. Furthermore, Mrgprb2 knockout (Mrgprb2^-/-) mice were used to determine the role of this pathway in a preclinical dextran sodium sulphate (DSS) colitis model.</div></div><div><h3>Results</h3><div>We found that Mrgprb2 acts as a novel MC degranulation pathway in a large subset of connective tissue MCs in the mouse distal colon. Acute DSS colitis induced a pronounced increase of Mrgprb2-expressing MCs, which were found in close association with Substance P-positive nerve fibers. Loss of Mrgprb2-mediated signaling impaired DSS-induced neutrophil influx and significantly impacted on acute colitis progression.</div></div><div><h3>Conclusions</h3><div>Our findings uncover a novel, IgE-independent MC degranulation pathway in the mouse colon that plays a central role in acute colitis pathophysiology, mainly by safeguarding acute colitis progression and severity in mice. This pseudo allergic, Mrgprb2-induced signaling is part of a hitherto unconsidered colonic neuro-immune pathway and might have significant potential for the further development of effective therapeutic treatment strategies for gastrointestinal disorders, such as ulcerative colitis.</div></div>","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":null,"pages":null},"PeriodicalIF":7.1,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2352345X24001462/pdfft?md5=29f04f0a676c97ff22d61f8cb141ebac&pid=1-s2.0-S2352345X24001462-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142047592","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}