Pub Date : 2026-03-11DOI: 10.1097/hep.0000000000001739
Nadim Mahmud, Max S. Schechter, Siqi Zhang, Catherine Mezzacappa, Pedro Ochoa-Allemant, David E. Kaplan, Marina Serper
Background and Aims: Guidelines recommend intravenous (IV) albumin after large-volume paracentesis to prevent post-paracentesis circulatory dysfunction and acute kidney injury (AKI). However, real-world effects of albumin on paracentesis outcomes in outpatient settings are understudied. We aimed to address this using national data from a well-established cirrhosis cohort. Methodology: This was a retrospective cohort study of Veterans with cirrhosis undergoing outpatient paracentesis. Albumin administration and paracentesis volumes were extracted, in addition to hospitalization for AKI within 7 days of outpatient paracentesis. Mixed-effects logistic regression identified factors associated with albumin administration and the association between albumin and incident AKI hospitalization. Results: Among 9,467 patients who received 56,941 outpatient paracentesis procedures, IV albumin was used 17% of the time. Use was higher with MELD-Na (OR 1.02, 95% CI 1.02-1.03, p <0.001), lower eGFR (OR 3.06 for <30 vs. ≥90 mL/min/1.73 m², 95% CI 2.64-3.54, p <0.001), and hepatic encephalopathy (OR 1.22, 95% CI 1.13-1.33, p <0.001). Albumin administration was associated with lower odds of AKI-related hospitalizations (OR 0.66, 95% CI 0.54–0.81, p <0.001) with greater effect observed in patients with lower eGFR (interaction p -value=0.03). In a subcohort of 48,401 procedures with available dosing information, higher-dose albumin (≥6-8 g/L removed) was associated with lower odds AKI hospitalization (OR 0.36, 95% CI 0.20-0.64, p =0.001) with similar associations noted irrespective of paracentesis volume. Conclusion: Albumin administration after outpatient paracentesis was associated with a reduced risk of hospitalization with AKI, with greater effect at lower eGFRs. Strategies that tailor albumin administration based on intravascular volume and hemodynamics should be prospectively tested.
背景和目的：指南推荐在大容量穿刺后静脉注射白蛋白以预防穿刺后循环功能障碍和急性肾损伤（AKI）。然而，白蛋白对门诊穿刺结果的实际影响尚未得到充分研究。我们的目的是通过一个完善的肝硬化队列的国家数据来解决这个问题。方法：这是一项对接受门诊穿刺的肝硬化退伍军人的回顾性队列研究。提取白蛋白给药量和穿刺量，并在门诊穿刺后7天内因AKI住院。混合效应logistic回归确定了与白蛋白给药相关的因素以及白蛋白与AKI住院事件之间的关联。结果：在接受56,941例门诊穿刺手术的9,467例患者中，静脉注射白蛋白的比例为17%。MELD-Na的使用率较高（OR 1.02, 95% CI 1.02-1.03, p <0.001）， eGFR较低（OR 3.06,≥90 mL/min/1.73 m²，95% CI 2.64-3.54, p <0.001），肝性脑病（OR 1.22, 95% CI 1.13-1.33, p <0.001）。白蛋白给药与aki相关住院的几率较低相关（OR 0.66, 95% CI 0.54-0.81, p <0.001），在eGFR较低的患者中观察到更大的影响（相互作用p值=0.03）。在一项包含48,401例可获得剂量信息的手术亚队列中，高剂量白蛋白（≥6-8 g/L）与AKI住院率较低相关（OR 0.36, 95% CI 0.20-0.64, p =0.001），且与穿刺容积无关。结论：门诊穿刺术后白蛋白给药与AKI住院风险降低相关，egfr较低时效果更明显。根据血管内容量和血流动力学来调整白蛋白给药的策略应该进行前瞻性试验。
{"title":"Intravenous albumin after outpatient paracentesis reduces risk of AKI hospitalization: A national cohort study","authors":"Nadim Mahmud, Max S. Schechter, Siqi Zhang, Catherine Mezzacappa, Pedro Ochoa-Allemant, David E. Kaplan, Marina Serper","doi":"10.1097/hep.0000000000001739","DOIUrl":"https://doi.org/10.1097/hep.0000000000001739","url":null,"abstract":"Background and Aims: Guidelines recommend intravenous (IV) albumin after large-volume paracentesis to prevent post-paracentesis circulatory dysfunction and acute kidney injury (AKI). However, real-world effects of albumin on paracentesis outcomes in outpatient settings are understudied. We aimed to address this using national data from a well-established cirrhosis cohort. Methodology: This was a retrospective cohort study of Veterans with cirrhosis undergoing outpatient paracentesis. Albumin administration and paracentesis volumes were extracted, in addition to hospitalization for AKI within 7 days of outpatient paracentesis. Mixed-effects logistic regression identified factors associated with albumin administration and the association between albumin and incident AKI hospitalization. Results: Among 9,467 patients who received 56,941 outpatient paracentesis procedures, IV albumin was used 17% of the time. Use was higher with MELD-Na (OR 1.02, 95% CI 1.02-1.03, <jats:italic toggle=\"yes\">p</jats:italic> <0.001), lower eGFR (OR 3.06 for <30 vs. ≥90 mL/min/1.73 m², 95% CI 2.64-3.54, <jats:italic toggle=\"yes\">p</jats:italic> <0.001), and hepatic encephalopathy (OR 1.22, 95% CI 1.13-1.33, <jats:italic toggle=\"yes\">p</jats:italic> <0.001). Albumin administration was associated with lower odds of AKI-related hospitalizations (OR 0.66, 95% CI 0.54–0.81, <jats:italic toggle=\"yes\">p</jats:italic> <0.001) with greater effect observed in patients with lower eGFR (interaction <jats:italic toggle=\"yes\">p</jats:italic> -value=0.03). In a subcohort of 48,401 procedures with available dosing information, higher-dose albumin (≥6-8 g/L removed) was associated with lower odds AKI hospitalization (OR 0.36, 95% CI 0.20-0.64, <jats:italic toggle=\"yes\">p</jats:italic> =0.001) with similar associations noted irrespective of paracentesis volume. Conclusion: Albumin administration after outpatient paracentesis was associated with a reduced risk of hospitalization with AKI, with greater effect at lower eGFRs. Strategies that tailor albumin administration based on intravascular volume and hemodynamics should be prospectively tested.","PeriodicalId":177,"journal":{"name":"Hepatology","volume":"15 1","pages":""},"PeriodicalIF":13.5,"publicationDate":"2026-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147393528","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-03-11DOI: 10.1097/hep.0000000000001740
Junyu Wu, Zhuofeng Jiang, Qiucheng Li, Chien-Shan Cheng, Yau-Tuen Chan, Ranna Yeerken, Junbang Chen, Pengde Lu, Zixin Feng, Hongchao Yuan, Lin Xu, Zhiqiang Meng, Yibin Feng, Hor-Yue Tan, Ning Wang
Background and Aims: Immune checkpoint blockade (ICB) shows therapeutic promise in hepatocellular carcinoma (HCC) but is associated with suboptimal responses in patients. Progenitor exhausted T (Tpex) cells are key responders to ICB, but the regulatory mechanisms regarding Tpex maintenance in HCC remain elusive. Approach and Results: Through an integrated analysis of HCC single-cell RNA-sequencing datasets, we constructed an exhausted CD8 + T cell atlas and identified FYN as a marker of Tpex cells in ICB responders. FYN deficiency in CD8 + T cells induced LCK hyperactivation, which drove terminal exhaustion under high-affinity antigen stimulation. Mechanistically, LCK hyperactivation disrupted metabolic homeostasis by triggering excessive glycolysis and impairing mitochondrial function in Tpex cells. Conversely, LCK inhibition elevated compensatory FYN activity, restored mitochondrial fitness and preserved Tpex cell stemness. In preclinical HCC models, transient LCK inhibition during T cell expansion enhanced adoptive cell therapy efficacy by increasing Tpex cell persistence and stemness. Besides, preemptive low-dose LCK inhibition prior to anti-PD1 therapy expanded the Tpex cell pool, reduced terminal exhaustion, and improved therapeutic outcomes. Conclusions: This study establishes the balance between SRC kinases FYN and LCK as a critical regulator of the terminal exhaustion of Tpex cell through metabolic reprogramming. The finding suggests that modulating the FYN/LCK kinase balance is a promising strategy to overcome immunotherapy resistance in HCC.
{"title":"FYN/LCK kinase balance as a metabolic switch orchestrates progenitor exhausted T Cell differentiation in hepatocellular carcinoma","authors":"Junyu Wu, Zhuofeng Jiang, Qiucheng Li, Chien-Shan Cheng, Yau-Tuen Chan, Ranna Yeerken, Junbang Chen, Pengde Lu, Zixin Feng, Hongchao Yuan, Lin Xu, Zhiqiang Meng, Yibin Feng, Hor-Yue Tan, Ning Wang","doi":"10.1097/hep.0000000000001740","DOIUrl":"https://doi.org/10.1097/hep.0000000000001740","url":null,"abstract":"Background and Aims: Immune checkpoint blockade (ICB) shows therapeutic promise in hepatocellular carcinoma (HCC) but is associated with suboptimal responses in patients. Progenitor exhausted T (Tpex) cells are key responders to ICB, but the regulatory mechanisms regarding Tpex maintenance in HCC remain elusive. Approach and Results: Through an integrated analysis of HCC single-cell RNA-sequencing datasets, we constructed an exhausted CD8 <jats:sup>+</jats:sup> T cell atlas and identified FYN as a marker of Tpex cells in ICB responders. FYN deficiency in CD8 <jats:sup>+</jats:sup> T cells induced LCK hyperactivation, which drove terminal exhaustion under high-affinity antigen stimulation. Mechanistically, LCK hyperactivation disrupted metabolic homeostasis by triggering excessive glycolysis and impairing mitochondrial function in Tpex cells. Conversely, LCK inhibition elevated compensatory FYN activity, restored mitochondrial fitness and preserved Tpex cell stemness. In preclinical HCC models, transient LCK inhibition during T cell expansion enhanced adoptive cell therapy efficacy by increasing Tpex cell persistence and stemness. Besides, preemptive low-dose LCK inhibition prior to anti-PD1 therapy expanded the Tpex cell pool, reduced terminal exhaustion, and improved therapeutic outcomes. Conclusions: This study establishes the balance between SRC kinases FYN and LCK as a critical regulator of the terminal exhaustion of Tpex cell through metabolic reprogramming. The finding suggests that modulating the FYN/LCK kinase balance is a promising strategy to overcome immunotherapy resistance in HCC.","PeriodicalId":177,"journal":{"name":"Hepatology","volume":"26 1","pages":""},"PeriodicalIF":13.5,"publicationDate":"2026-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147393489","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-03-11DOI: 10.1097/hep.0000000000001710
Christina Schrader, Malin Fromme, Paul Ellis, Audrey Payancé, Mattias Mandorfer, Jan Stolk, Bart van Hoek, Katrine H. Thorhauge, Monica Pons, Marc Miravitlles, Guido Stirnimann, Sona Frankova, Jan Sperl, Andreas E. Kremer, Katharina Remih, Emily K. Weber, Lorenz Balcar, Annelot D. Sark, Benedikt Schaefer, Joanna Chorostowska-Wynimko, Elmar Aigner, Sophie Gensluckner, Heike Bantel, Jef Verbeek, Zoe Mariño, Rohit Loomba, Heinz Zoller, Michael Trauner, Joan Genesca, Virginia Clark, Aleksander Krag, Noel G. McElvaney, William J. Griffiths, Alice M. Turner, Pavel Strnad
Background and Aims: Severe (Pi*ZZ) and heterozygous (Pi*MZ) alpha-1 antitrypsin deficiency (AATD) confer increased liver- and lung-related mortality, but the phenotype is highly variable. We aimed to evaluate the impact of obesity and diabetes mellitus on individuals with/without AATD. Approach and Results: Cohort 1 prospectively recruited 1678 Pi*ZZ adults from an international initiative with a systematic liver assessment. 983 participants had a longitudinal follow-up. The data were compared to 16,768 Pi*MZ and 415,208 non-AATD individuals from the United Kingdom Biobank (cohort 2). Findings were ascertained by multivariable adjustment and propensity score matching. At baseline, diabetes was present in 52 (3%), overweight (BMI 25.0-29.9 kg/m 2 ) in 540 (52%) and obesity (BMI≥30 kg/m 2 ) in 266 (32%) Pi*ZZ adults. Pi*ZZ individuals with diabetes showed higher transaminases and surrogates of advanced liver fibrosis (APRI≥1.0, LSM≥15 kPa) were four to six times more common (adjusted Odds Ratio (aOR) 5.7/4.3, p <0.01). Elevated transaminases were rare among lean Pi*ZZ subjects, but more common in overweight (aOR 1.5/2.0) and obese Pi*ZZ participants (aOR 2.1/2.9). APRI≥1.0 was more than four times elevated in obese vs. lean Pi*ZZ individuals (aOR 4.1, p <0.001). During a median follow-up of 4.2 years, 54 Pi*ZZ participants experienced a hepatic and 64 a pulmonary endpoint. While Pi*ZZ participants with diabetes/obesity had an increased risk of hepatic endpoints (aHR 6.03/3.38, p <0.001) compared with non-diabetic/lean Pi*ZZ subjects, overweight was associated with a decreased risk of pulmonary endpoints (aHR 0.45, p =0.004). Conclusions: Our data demonstrate the interaction between genetic and metabolic risk factors in AATD and provide evidence for patient management.
背景和目的：严重（Pi*ZZ）和杂合(Pi*MZ) α -1抗胰蛋白酶缺乏症（AATD）会增加肝脏和肺部相关的死亡率，但其表型是高度可变的。我们旨在评估肥胖和糖尿病对患有/不患有AATD的个体的影响。方法和结果：队列1前瞻性地从一项系统肝脏评估的国际倡议中招募了1678名Pi*ZZ成年人。983名参与者进行了纵向随访。将数据与来自英国生物银行（队列2）的16,768名Pi*MZ和415,208名非aatd个体进行比较。通过多变量调整和倾向评分匹配来确定研究结果。基线时，52名（3%）Pi*ZZ成人患有糖尿病，540名（52%）存在超重（BMI 25.0-29.9 kg/ m2）， 266名（32%）存在肥胖（BMI≥30 kg/ m2）。Pi*ZZ糖尿病患者转氨酶较高，晚期肝纤维化（APRI≥1.0,LSM≥15 kPa）的代物发生率为4 ~ 6倍（校正优势比（aOR） 5.7/4.3, p <0.01）。转氨酶升高在瘦Pi*ZZ受试者中罕见，但在超重（aOR 1.5/2.0）和肥胖Pi*ZZ受试者（aOR 2.1/2.9）中更为常见。肥胖Pi*ZZ个体的APRI≥1.0比瘦弱Pi*ZZ个体高4倍以上（aOR 4.1, p <0.001）。在4.2年的中位随访期间，54名Pi*ZZ参与者经历了肝脏终点和64名肺部终点。与非糖尿病/瘦Pi*ZZ受试者相比，患有糖尿病/肥胖的Pi*ZZ受试者肝脏终点风险增加（aHR 6.03/3.38, p <0.001），而超重与肺部终点风险降低相关（aHR 0.45, p =0.004）。结论：我们的数据显示了AATD中遗传和代谢危险因素之间的相互作用，并为患者管理提供了证据。
{"title":"Original research: Amplification of genetic and metabolic factors in alpha-1 antitrypsin deficiency","authors":"Christina Schrader, Malin Fromme, Paul Ellis, Audrey Payancé, Mattias Mandorfer, Jan Stolk, Bart van Hoek, Katrine H. Thorhauge, Monica Pons, Marc Miravitlles, Guido Stirnimann, Sona Frankova, Jan Sperl, Andreas E. Kremer, Katharina Remih, Emily K. Weber, Lorenz Balcar, Annelot D. Sark, Benedikt Schaefer, Joanna Chorostowska-Wynimko, Elmar Aigner, Sophie Gensluckner, Heike Bantel, Jef Verbeek, Zoe Mariño, Rohit Loomba, Heinz Zoller, Michael Trauner, Joan Genesca, Virginia Clark, Aleksander Krag, Noel G. McElvaney, William J. Griffiths, Alice M. Turner, Pavel Strnad","doi":"10.1097/hep.0000000000001710","DOIUrl":"https://doi.org/10.1097/hep.0000000000001710","url":null,"abstract":"Background and Aims: Severe (Pi*ZZ) and heterozygous (Pi*MZ) alpha-1 antitrypsin deficiency (AATD) confer increased liver- and lung-related mortality, but the phenotype is highly variable. We aimed to evaluate the impact of obesity and diabetes mellitus on individuals with/without AATD. Approach and Results: Cohort 1 prospectively recruited 1678 Pi*ZZ adults from an international initiative with a systematic liver assessment. 983 participants had a longitudinal follow-up. The data were compared to 16,768 Pi*MZ and 415,208 non-AATD individuals from the United Kingdom Biobank (cohort 2). Findings were ascertained by multivariable adjustment and propensity score matching. At baseline, diabetes was present in 52 (3%), overweight (BMI 25.0-29.9 kg/m <jats:sup>2</jats:sup> ) in 540 (52%) and obesity (BMI≥30 kg/m <jats:sup>2</jats:sup> ) in 266 (32%) Pi*ZZ adults. Pi*ZZ individuals with diabetes showed higher transaminases and surrogates of advanced liver fibrosis (APRI≥1.0, LSM≥15 kPa) were four to six times more common (adjusted Odds Ratio (aOR) 5.7/4.3, <jats:italic toggle=\"yes\">p</jats:italic> <0.01). Elevated transaminases were rare among lean Pi*ZZ subjects, but more common in overweight (aOR 1.5/2.0) and obese Pi*ZZ participants (aOR 2.1/2.9). APRI≥1.0 was more than four times elevated in obese vs. lean Pi*ZZ individuals (aOR 4.1, <jats:italic toggle=\"yes\">p</jats:italic> <0.001). During a median follow-up of 4.2 years, 54 Pi*ZZ participants experienced a hepatic and 64 a pulmonary endpoint. While Pi*ZZ participants with diabetes/obesity had an increased risk of hepatic endpoints (aHR 6.03/3.38, <jats:italic toggle=\"yes\">p</jats:italic> <0.001) compared with non-diabetic/lean Pi*ZZ subjects, overweight was associated with a decreased risk of pulmonary endpoints (aHR 0.45, <jats:italic toggle=\"yes\">p</jats:italic> =0.004). Conclusions: Our data demonstrate the interaction between genetic and metabolic risk factors in AATD and provide evidence for patient management.","PeriodicalId":177,"journal":{"name":"Hepatology","volume":"33 1","pages":""},"PeriodicalIF":13.5,"publicationDate":"2026-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147393529","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-03-09DOI: 10.1097/hep.0000000000001737
Nana Yan, Yangliu Xia, Yang Zhang, Vorthon Sawaswong, Xi Xu, Yoshifumi Saito, Ravikanth Nanduri, Mengge Dai, Daisuke Aibara, Kristopher W. Krausz, Shogo Takahashi, Brandon J. Peiffer, Maria A. Parra, Zhaoli Sun, Haiping Hao, Tingting Yan, Frank J. Gonzalez
Background and aims: Alcohol-associated liver disease (ALD) represents a global health burden with limited therapeutic strategies. While the hepatocyte transcription factor CCAAT/enhancer-binding protein α (CEBPA) regulates hepatic gene expression and liver fibrosis, its role in ALD pathogenesis remains undefined. Here, hepatocyte CEBPA was examined for its modulation of alcohol-associated hepatic steatosis and ALD. Approach and Results: Hepatocyte-specific CEBPA knockout mice, AAV transduction studies and reporter gene assays, were carried out using acute and chronic mouse ALD models. Western blotting was performed on liver tissues from human ALD patients. Hepatic CEBPA expression decreased during ALD progression in human patient cohorts. Hepatocyte-specific Cebpa -knockout mice exhibited exacerbated alcohol-associated steatosis in both the acute and chronic ALD models. Inducible ablation of CEBPA in hepatocytes during late-stage ALD, accelerated disease progression, demonstrating the persistent protective function of CEBPA. Global transcriptomics identified Orm1 encoding orosomucoid 1 (ORM1) as the top CEBPA-upregulated gene in hepatocytes, while reporter assays and chromatin immunoprecipitation revealed that CEBPA directly activates Orm1 transcription by binding CEBPA response elements upstream of the Orm1 promoter. Loss of hepatocyte ORM1 potentiated the severity of ALD in mice. Conversely, restoring CEBPA or ORM1 via intravenous AAV8 delivery or administering recombinant ORM1 protein, rescued hepatic lipid accumulation and reduced disease progression. Consistently, serum ORM1, a hepatocyte-secreted hepatokine, inversely correlated with ALD severity in patients. Conclusions: These findings identify the hepatocyte CEBPA-ORM1 axis as a critical suppressor of ALD, offering therapeutic targets and nominating serum ORM1 as a potential biomarker for staging ALD severity.
{"title":"Hepatocyte CEBPA-ORM1 axis restricts alcohol-associated liver disease","authors":"Nana Yan, Yangliu Xia, Yang Zhang, Vorthon Sawaswong, Xi Xu, Yoshifumi Saito, Ravikanth Nanduri, Mengge Dai, Daisuke Aibara, Kristopher W. Krausz, Shogo Takahashi, Brandon J. Peiffer, Maria A. Parra, Zhaoli Sun, Haiping Hao, Tingting Yan, Frank J. Gonzalez","doi":"10.1097/hep.0000000000001737","DOIUrl":"https://doi.org/10.1097/hep.0000000000001737","url":null,"abstract":"Background and aims: Alcohol-associated liver disease (ALD) represents a global health burden with limited therapeutic strategies. While the hepatocyte transcription factor CCAAT/enhancer-binding protein α (CEBPA) regulates hepatic gene expression and liver fibrosis, its role in ALD pathogenesis remains undefined. Here, hepatocyte CEBPA was examined for its modulation of alcohol-associated hepatic steatosis and ALD. Approach and Results: Hepatocyte-specific CEBPA knockout mice, AAV transduction studies and reporter gene assays, were carried out using acute and chronic mouse ALD models. Western blotting was performed on liver tissues from human ALD patients. Hepatic CEBPA expression decreased during ALD progression in human patient cohorts. Hepatocyte-specific <jats:italic toggle=\"yes\">Cebpa</jats:italic> -knockout mice exhibited exacerbated alcohol-associated steatosis in both the acute and chronic ALD models. Inducible ablation of CEBPA in hepatocytes during late-stage ALD, accelerated disease progression, demonstrating the persistent protective function of CEBPA. Global transcriptomics identified <jats:italic toggle=\"yes\">Orm1</jats:italic> encoding orosomucoid 1 (ORM1) as the top CEBPA-upregulated gene in hepatocytes, while reporter assays and chromatin immunoprecipitation revealed that CEBPA directly activates <jats:italic toggle=\"yes\">Orm1</jats:italic> transcription by binding CEBPA response elements upstream of the <jats:italic toggle=\"yes\">Orm1</jats:italic> promoter. Loss of hepatocyte ORM1 potentiated the severity of ALD in mice. Conversely, restoring CEBPA or ORM1 via intravenous AAV8 delivery or administering recombinant ORM1 protein, rescued hepatic lipid accumulation and reduced disease progression. Consistently, serum ORM1, a hepatocyte-secreted hepatokine, inversely correlated with ALD severity in patients. Conclusions: These findings identify the hepatocyte CEBPA-ORM1 axis as a critical suppressor of ALD, offering therapeutic targets and nominating serum ORM1 as a potential biomarker for staging ALD severity.","PeriodicalId":177,"journal":{"name":"Hepatology","volume":"40 1","pages":""},"PeriodicalIF":13.5,"publicationDate":"2026-03-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147380866","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-03-06DOI: 10.1097/hep.0000000000001732
Sheikh Abdul Rahman,Sailaja Gangadhara,John Gridley,Uchurappa Mala,Elizabeth J Elrod,Nathalie Bédard,Julie Bruneau,Naglaa H Shoukry,Arash Grakoui,Rama Rao Amara
The hepatitis C virus (HCV) is a major cause of liver cirrhosis and cancer in humans, and an effective vaccine is urgently needed. Here, we evaluated the immunogenicity of a DNA prime and modified vaccinia Ankara (MVA) boost vaccine expressing H77 genotype 1a HCV immunogens to induce both T and B cell responses. The non-structural (NS) immunogens expressed NS3, NS4, and NS5. The structural plus p7 immunogen (S-p7) expressed Core, E1, E2 and p7. We tested the immunogenicity of these vaccines in mice and rhesus macaques (RMs) with 2 or 3 doses of DNA followed by 1 or 2 doses of MVA. The NS immunogens induced CD4 and CD8 T cell responses against multiple NS proteins with a dominant CD4 T cell response to NS3 and NS5, and a dominant CD8 T cell response to NS3. The S-p7 immunogen induced E2-binding IgG titer with neutralizing activity against autologous and heterologous HCV pseudovirus particles. Additionally, the S-p7 immunogen induced a CD4 and CD8 T cell response directed against E1 (0.08% and 0.09%, respectively) and E2 (0.13% and 0.18%, respectively) in RMs. Co-delivery of S-p7 and NS vaccines elicited a T cell response against the majority of HCV proteins, which was comparable to the T cell response observed in humans with HCV resolution. These findings show that the DNA/MVA prime/boost vaccination induces a strong and broad CD4 and CD8 T cell response to multiple HCV proteins and a neutralizing antibody response. These results aid in the development of vaccines for HCV.
{"title":"T and B cell targeting DNA/MVA HCV vaccines induce strong and broad cellular and humoral immunity in mice and rhesus macaques.","authors":"Sheikh Abdul Rahman,Sailaja Gangadhara,John Gridley,Uchurappa Mala,Elizabeth J Elrod,Nathalie Bédard,Julie Bruneau,Naglaa H Shoukry,Arash Grakoui,Rama Rao Amara","doi":"10.1097/hep.0000000000001732","DOIUrl":"https://doi.org/10.1097/hep.0000000000001732","url":null,"abstract":"The hepatitis C virus (HCV) is a major cause of liver cirrhosis and cancer in humans, and an effective vaccine is urgently needed. Here, we evaluated the immunogenicity of a DNA prime and modified vaccinia Ankara (MVA) boost vaccine expressing H77 genotype 1a HCV immunogens to induce both T and B cell responses. The non-structural (NS) immunogens expressed NS3, NS4, and NS5. The structural plus p7 immunogen (S-p7) expressed Core, E1, E2 and p7. We tested the immunogenicity of these vaccines in mice and rhesus macaques (RMs) with 2 or 3 doses of DNA followed by 1 or 2 doses of MVA. The NS immunogens induced CD4 and CD8 T cell responses against multiple NS proteins with a dominant CD4 T cell response to NS3 and NS5, and a dominant CD8 T cell response to NS3. The S-p7 immunogen induced E2-binding IgG titer with neutralizing activity against autologous and heterologous HCV pseudovirus particles. Additionally, the S-p7 immunogen induced a CD4 and CD8 T cell response directed against E1 (0.08% and 0.09%, respectively) and E2 (0.13% and 0.18%, respectively) in RMs. Co-delivery of S-p7 and NS vaccines elicited a T cell response against the majority of HCV proteins, which was comparable to the T cell response observed in humans with HCV resolution. These findings show that the DNA/MVA prime/boost vaccination induces a strong and broad CD4 and CD8 T cell response to multiple HCV proteins and a neutralizing antibody response. These results aid in the development of vaccines for HCV.","PeriodicalId":177,"journal":{"name":"Hepatology","volume":"418 1","pages":""},"PeriodicalIF":13.5,"publicationDate":"2026-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147368245","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-03-06DOI: 10.1097/hep.0000000000001736
Natalia Hermán-Sánchez,Maite G Fernández-Barrena,Paloma E Alañón-Martínez,Iker Uriarte,Reuven Agami,Raúl M Luque,Matías A Avila,Manuel Rodriguez-Perálvarez,Juan L López-Cánovas,Manuel D Gahete
BACKGROUNDAminoacyl-tRNA synthetases (ARSs) exert canonical and emerging non-canonical roles in cancer. Given the frequent alterations in aspartate metabolism in hepatocellular carcinoma (HCC), we investigated the clinical and functional significance of aspartyl-tRNA synthetase (DARS1) in HCC.METHODSDARS1 expression was evaluated in tumor and matched non-tumoral tissues, in silico cohorts, and plasma samples. Functional assays were performed in liver cancer cell lines after genetic and pharmacological modulation of DARS1. In vivo validation was conducted using xenograft and orthotopic tumor models. Protein interactors of DARS1 were characterized by quantitative proteomics and confirmed by biochemical approaches.RESULTSDARS1 abundance was increased in HCC, especially in highly aggressive tumours, and in plasma from HCC patients. DARS1 overexpression increased aggressiveness in vitro and xenograft and orthotopic tumour formation in vivo, while genetic and pharmacological blockade of DARS1 impaired stemness in vitro without affecting normal-like cells. Proteomic profiling revealed a significant enrichment of high-aspartate proteins in DARS1-overexpressing cells, demonstrating a reshaping of the HCC proteome. Beyond its canonical role, DARS1 was found in the nucleus interacting with members of the SAGA transcriptional co-activator complex, including SUPT7L. This interaction affected MYC regulation, as DARS1 depletion reduced MYC protein levels, increased its phosphorylation, and enhanced drug-induced senescence, linking DARS1-SAGA activity to MYC-driven oncogenic pathways.CONCLUSIONSDARS1 is frequently overexpressed in HCC and detectable in plasma, supporting its potential as liquid biopsy biomarker. Functionally, DARS1 represents a novel vulnerability of HCC, acting through both proteome reshaping and non-canonical nuclear interactions with the SAGA complex that modulate MYC activity.
{"title":"Aspartyl-tRNA synthetase 1 (DARS1) reshapes hepatocellular carcinoma proteome and promotes aggressiveness through non-canonical SAGA-MYC signalling modulation.","authors":"Natalia Hermán-Sánchez,Maite G Fernández-Barrena,Paloma E Alañón-Martínez,Iker Uriarte,Reuven Agami,Raúl M Luque,Matías A Avila,Manuel Rodriguez-Perálvarez,Juan L López-Cánovas,Manuel D Gahete","doi":"10.1097/hep.0000000000001736","DOIUrl":"https://doi.org/10.1097/hep.0000000000001736","url":null,"abstract":"BACKGROUNDAminoacyl-tRNA synthetases (ARSs) exert canonical and emerging non-canonical roles in cancer. Given the frequent alterations in aspartate metabolism in hepatocellular carcinoma (HCC), we investigated the clinical and functional significance of aspartyl-tRNA synthetase (DARS1) in HCC.METHODSDARS1 expression was evaluated in tumor and matched non-tumoral tissues, in silico cohorts, and plasma samples. Functional assays were performed in liver cancer cell lines after genetic and pharmacological modulation of DARS1. In vivo validation was conducted using xenograft and orthotopic tumor models. Protein interactors of DARS1 were characterized by quantitative proteomics and confirmed by biochemical approaches.RESULTSDARS1 abundance was increased in HCC, especially in highly aggressive tumours, and in plasma from HCC patients. DARS1 overexpression increased aggressiveness in vitro and xenograft and orthotopic tumour formation in vivo, while genetic and pharmacological blockade of DARS1 impaired stemness in vitro without affecting normal-like cells. Proteomic profiling revealed a significant enrichment of high-aspartate proteins in DARS1-overexpressing cells, demonstrating a reshaping of the HCC proteome. Beyond its canonical role, DARS1 was found in the nucleus interacting with members of the SAGA transcriptional co-activator complex, including SUPT7L. This interaction affected MYC regulation, as DARS1 depletion reduced MYC protein levels, increased its phosphorylation, and enhanced drug-induced senescence, linking DARS1-SAGA activity to MYC-driven oncogenic pathways.CONCLUSIONSDARS1 is frequently overexpressed in HCC and detectable in plasma, supporting its potential as liquid biopsy biomarker. Functionally, DARS1 represents a novel vulnerability of HCC, acting through both proteome reshaping and non-canonical nuclear interactions with the SAGA complex that modulate MYC activity.","PeriodicalId":177,"journal":{"name":"Hepatology","volume":"19 1","pages":""},"PeriodicalIF":13.5,"publicationDate":"2026-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147368243","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-03-04DOI: 10.1097/HEP.0000000000001717
Samer Gawrieh, Jordan E Lake, Paula Debroy, Julia A Sjoquist, Montreca Robison, Mark Tann, Fatih Akisik, Surya S Bhamidipalli, Chandan K Saha, Kimon Zachary, Gregory K Robbins, Samir K Gupta, Raymond T Chung, Naga Chalasani, Kathleen E Corey
{"title":"Erratum: Burden of fatty liver and hepatic fibrosis in persons with HIV: A diverse cross-sectional US multicenter study.","authors":"Samer Gawrieh, Jordan E Lake, Paula Debroy, Julia A Sjoquist, Montreca Robison, Mark Tann, Fatih Akisik, Surya S Bhamidipalli, Chandan K Saha, Kimon Zachary, Gregory K Robbins, Samir K Gupta, Raymond T Chung, Naga Chalasani, Kathleen E Corey","doi":"10.1097/HEP.0000000000001717","DOIUrl":"https://doi.org/10.1097/HEP.0000000000001717","url":null,"abstract":"","PeriodicalId":177,"journal":{"name":"Hepatology","volume":" ","pages":""},"PeriodicalIF":15.8,"publicationDate":"2026-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147353088","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
BACKGROUNDOncostatin M (OSM) has been shown to contribute to metabolic dysfunction-associated steatohepatitis (MASH) progression to hepatocellular carcinoma (HCC). Here we investigated its role in shaping an immunosuppressive tumor microenvironment (TIME) in MASH-HCCs.APPROACHOSM role was investigated through combined analyses of MASLD/MASH patients with or without HCC, MASH-related HCCs originating in wild type and hepatocyte-specific OSM receptor-β (hOSMRβ-/-) deficient mice and in vitro experiments performed on liver cancer and immune cell lines.RESULTSAnalysis of OSM-expressing HCC patients with mixed etiology (TCGA-database) revealed a positive correlation between OSM transcripts and those of several TIME markers. A similar pattern was also observed in murine MASH-HCC tumors. hOSMRβ-/- mice had significantly reduced tumor volume and weight without altering macrophage infiltration and OSM production. However, TIME markers transcripts were lower in HCCs from hOSMRβ-/- mice. These effects associated with a lowering in tumor STAT3 phosphorylation and COX-2 activity. Single-cell RNAseq analysis of human HCCs identified malignant hepatocyte as source of CCL15, a cytokine associated with immunosuppression in HCCs. Circulating CCL15 was markedly elevated in either human and rodent MASH-HCCs and significantly reduced by hOSMRβ deletion. Blocking autocrine OSM signaling in HepG2 or Huh7 cells overexpressing OSM reduced STAT3 phosphorylation, CCL15 production and prevented TIME markers expression by co-cultured macrophage-derived THP1 cells.CONCLUSIONSOur findings provide compelling evidence for an autocrine role of OSM/OSMRβ axis in promoting CCL15 production by tumor cells which, in turn, stimulates an immunosuppressive TIME in MASH-HCCs, suggesting OSM as a potential therapeutic target for HCC treatment.
背景：doncostatin M （OSM）已被证明与代谢功能障碍相关的脂肪性肝炎（MASH）进展为肝细胞癌（HCC）有关。在这里，我们研究了它在mash - hcc中形成免疫抑制肿瘤微环境（TIME）的作用。通过对伴有或不伴有HCC的MASLD/MASH患者、源自野生型和肝细胞特异性OSM受体-β (hOSMRβ-/-)缺陷小鼠的MASH相关HCC以及肝癌和免疫细胞系的体外实验，研究了APPROACHOSM的作用。结果对混合病因表达OSM的HCC患者的分析（tcga数据库）显示OSM转录物与多个TIME标记物呈正相关。在小鼠MASH-HCC肿瘤中也观察到类似的模式。在不改变巨噬细胞浸润和OSM产生的情况下，hOSMRβ-/-小鼠的肿瘤体积和重量显著减少。然而，在来自hOSMRβ-/-小鼠的hcc中，TIME标记物转录较低。这些作用与肿瘤STAT3磷酸化和COX-2活性的降低有关。人类hcc的单细胞RNAseq分析发现，恶性肝细胞是CCL15的来源，CCL15是一种与hcc免疫抑制相关的细胞因子。在人和啮齿类msh - hcc中，循环CCL15显著升高，hOSMRβ缺失后循环CCL15显著降低。在过表达OSM的HepG2或Huh7细胞中，阻断自分泌OSM信号传导可减少STAT3磷酸化、CCL15的产生，并阻止共培养巨噬细胞来源的THP1细胞表达TIME标记物。结论本研究结果提供了令人信服的证据，证明OSM/OSMRβ轴在促进肿瘤细胞产生CCL15中的自分泌作用，进而刺激msh -HCC中的免疫抑制TIME，提示OSM可能是HCC治疗的潜在治疗靶点。
{"title":"The role of OSM/OSMRβ axis in shaping the tumor microenvironment favouring MASLD-Related HCC immune evasion.","authors":"Jessica Nurcis,Beatrice Foglia,Chiara Rosso,Alessia Provera,Cristina Vecchio,Marina Maggiora,Alessandro Gambella,Ugo Chianese,Claudia Bocca,Gian Paolo Caviglia,Rosaria Benedetti,Erica Novo,Francesca Bossi,Francesca Doto,Marta Anna Kowalik,Andrea Caddeo,Patrizia Carucci,Silvia Gaia,Renato Romagnoli,Alessio Menconi,Ignazia Tusa,Elisabetta Rovida,Andrea Perra,Elisabetta Bugianesi,Lucia Altucci,Emanuele Albano,Maurizio Parola,Salvatore Sutti,Stefania Cannito","doi":"10.1097/hep.0000000000001733","DOIUrl":"https://doi.org/10.1097/hep.0000000000001733","url":null,"abstract":"BACKGROUNDOncostatin M (OSM) has been shown to contribute to metabolic dysfunction-associated steatohepatitis (MASH) progression to hepatocellular carcinoma (HCC). Here we investigated its role in shaping an immunosuppressive tumor microenvironment (TIME) in MASH-HCCs.APPROACHOSM role was investigated through combined analyses of MASLD/MASH patients with or without HCC, MASH-related HCCs originating in wild type and hepatocyte-specific OSM receptor-β (hOSMRβ-/-) deficient mice and in vitro experiments performed on liver cancer and immune cell lines.RESULTSAnalysis of OSM-expressing HCC patients with mixed etiology (TCGA-database) revealed a positive correlation between OSM transcripts and those of several TIME markers. A similar pattern was also observed in murine MASH-HCC tumors. hOSMRβ-/- mice had significantly reduced tumor volume and weight without altering macrophage infiltration and OSM production. However, TIME markers transcripts were lower in HCCs from hOSMRβ-/- mice. These effects associated with a lowering in tumor STAT3 phosphorylation and COX-2 activity. Single-cell RNAseq analysis of human HCCs identified malignant hepatocyte as source of CCL15, a cytokine associated with immunosuppression in HCCs. Circulating CCL15 was markedly elevated in either human and rodent MASH-HCCs and significantly reduced by hOSMRβ deletion. Blocking autocrine OSM signaling in HepG2 or Huh7 cells overexpressing OSM reduced STAT3 phosphorylation, CCL15 production and prevented TIME markers expression by co-cultured macrophage-derived THP1 cells.CONCLUSIONSOur findings provide compelling evidence for an autocrine role of OSM/OSMRβ axis in promoting CCL15 production by tumor cells which, in turn, stimulates an immunosuppressive TIME in MASH-HCCs, suggesting OSM as a potential therapeutic target for HCC treatment.","PeriodicalId":177,"journal":{"name":"Hepatology","volume":"95 1","pages":""},"PeriodicalIF":13.5,"publicationDate":"2026-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147350580","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
BACKGROUND AND AIMSWhile gemcitabine/cisplatin (GC) combined with anti-PD-L1 is a first-line regimen for advanced intrahepatic cholangiocarcinoma (ICC), efficacy remains limited and toxicity significant, highlighting the need to optimize therapeutic strategy. We sought to investigate whether low-dose GC (LDGC) could unleash anti-PD-L1-mediated antitumor immunity along with reduced toxicity.APPROACH AND RESULTSMultiple preclinical ICC mouse models were used to assess the anti-tumor efficacy and toxicity of LDGC combined with anti-PD-L1. Mechanisms were investigated via single-cell RNA sequencing, flow cytometry, and in vivo/vitro functional assays. Clinical correlation was evaluated in patient-derived tumor fragments and a pilot clinical trial in ICC patients. LDGC combined with anti-PD-L1 treatment efficiently improved tumor immune microenvironment (TIME) through reducing immunosuppressive SPP1+ tumor-associated macrophages (TAMs) while promoting CD8⁺ T cell infiltration and cytotoxicity. LDGC reprograms the interplay between STAT1 and STAT3 transcriptional pathways in TAMs, thereby reducing SPP1 expression and weakening the inhibitory effect of the SPP1-VLA-4 signaling axis on CD8+ T cell, ultimately enhancing T cell cytotoxicity and sensitizing antitumor response to anti-PD-L1. Furthermore, the ICC patients exhibited superior response and tolerance to LDGC combined with immunotherapy.CONCLUSIONSThis study highlights that LDGC remodels the immunosuppressive microenvironment and potentiates anti-PD-L1 therapy, providing a rational regimen for ICC.
{"title":"Low-dose chemotherapy remodels hepatic immune landscape and potentiates anti-tumor response to immune checkpoint blockade in cholangiocarcinoma.","authors":"Liang Zhixing,Shanshan Liu,Haoyuan Yu,Lin Yuxi,Kun Li,Siqi Li,Shi Mengchen,Wang Xiangyang,Yongwei Hu,Chenghao Zhao,Lou Zhenbang,Jiang Peng,Wang Chuan,Liu Wei,Shuhong Yi,Shuqun Cheng,Cao Yingjiao,Hua Li,Yang Yang,Linsen Ye","doi":"10.1097/hep.0000000000001735","DOIUrl":"https://doi.org/10.1097/hep.0000000000001735","url":null,"abstract":"BACKGROUND AND AIMSWhile gemcitabine/cisplatin (GC) combined with anti-PD-L1 is a first-line regimen for advanced intrahepatic cholangiocarcinoma (ICC), efficacy remains limited and toxicity significant, highlighting the need to optimize therapeutic strategy. We sought to investigate whether low-dose GC (LDGC) could unleash anti-PD-L1-mediated antitumor immunity along with reduced toxicity.APPROACH AND RESULTSMultiple preclinical ICC mouse models were used to assess the anti-tumor efficacy and toxicity of LDGC combined with anti-PD-L1. Mechanisms were investigated via single-cell RNA sequencing, flow cytometry, and in vivo/vitro functional assays. Clinical correlation was evaluated in patient-derived tumor fragments and a pilot clinical trial in ICC patients. LDGC combined with anti-PD-L1 treatment efficiently improved tumor immune microenvironment (TIME) through reducing immunosuppressive SPP1+ tumor-associated macrophages (TAMs) while promoting CD8⁺ T cell infiltration and cytotoxicity. LDGC reprograms the interplay between STAT1 and STAT3 transcriptional pathways in TAMs, thereby reducing SPP1 expression and weakening the inhibitory effect of the SPP1-VLA-4 signaling axis on CD8+ T cell, ultimately enhancing T cell cytotoxicity and sensitizing antitumor response to anti-PD-L1. Furthermore, the ICC patients exhibited superior response and tolerance to LDGC combined with immunotherapy.CONCLUSIONSThis study highlights that LDGC remodels the immunosuppressive microenvironment and potentiates anti-PD-L1 therapy, providing a rational regimen for ICC.","PeriodicalId":177,"journal":{"name":"Hepatology","volume":"1 1","pages":""},"PeriodicalIF":13.5,"publicationDate":"2026-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147350532","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-03-01Epub Date: 2026-02-17DOI: 10.1097/HEP.0000000000001659
Prabhat Kumar, Juan Pablo Arab
{"title":"Rethinking liver transplant allocation: Balancing urgency and utility.","authors":"Prabhat Kumar, Juan Pablo Arab","doi":"10.1097/HEP.0000000000001659","DOIUrl":"10.1097/HEP.0000000000001659","url":null,"abstract":"","PeriodicalId":177,"journal":{"name":"Hepatology","volume":"83 3","pages":"427-428"},"PeriodicalIF":15.8,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146218067","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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