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Deng SS, Zhu YP, Chen ZT, Li W. Application progress of early nutrition intervention in patients with hepatocellular carcinoma after liver transplantation. World J Gastrointest Surg 2025; 17:100321. [PMID: 40162388 PMCID: PMC11948105 DOI: 10.4240/wjgs.v17.i3.100321] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/11/2024] [Revised: 12/01/2024] [Accepted: 01/09/2025] [Indexed: 02/24/2025] Open
Abstract
Liver transplantation, as an effective therapy for patients with liver cancer, plays an important role in improving the quality of life of patients. However, the complexity and trauma of liver transplantation can easily lead to the occurrence of malnutrition in patients, and then increase the risk of postoperative complications, which has aroused widespread clinical attention. Reasonable nutritional support can not only maintain the stability of the body's internal environment, reduce the occurrence of complications, but also promote the recovery of liver and other organ functions. In recent years, with the in-depth understanding of nutritional metabolism after liver transplantation, the application of enteral nutrition and parenteral nutrition in nutritional support after liver transplantation has been increasingly extensive and achieved remarkable results. This paper discusses the effect of early postoperative nutritional intervention on patients with liver cancer and liver transplantation, and combined with its mechanism of action, can better understand the effectiveness of intervention, and provide reference for the development of scientific and reasonable nutritional support programs in clinical practice.
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Affiliation(s)
- Shan-Shan Deng
- Department of Medical Oncology, Shulan (Hangzhou) Hospital Affiliated to Zhejiang Shuren University Shulan International, Medical College, Hangzhou 310022, Zhejiang Province, China
| | - Yu-Ping Zhu
- Department of Medical Oncology, Shulan (Hangzhou) Hospital Affiliated to Zhejiang Shuren University Shulan International, Medical College, Hangzhou 310022, Zhejiang Province, China
| | - Zhi-Tao Chen
- Department of Hepatobiliary Pancreatic Surgery, Shulan (Hangzhou) Hospital Affiliated to Zhejiang Shuren University Shulan International, Medical College, Hangzhou 310022, Zhejiang Province, China
| | - Wan Li
- Department of Critical Care Medicine, Shulan (Hangzhou) Hospital Affiliated to Zhejiang Shuren University Shulan International, Medical College, Hangzhou 310022, Zhejiang Province, China
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Liu X, Shi J, Wu M, Gao J, Zhang Y, Guo W, Zhang S. Betaine-homocysteine methyltransferase attenuates liver ischemia-reperfusion injury by targeting TAK1. FASEB J 2025; 39:e70349. [PMID: 39854060 DOI: 10.1096/fj.202402239rr] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2024] [Revised: 12/30/2024] [Accepted: 01/15/2025] [Indexed: 01/26/2025]
Abstract
Liver ischemia-reperfusion (IR) injury is a common complication following liver surgery, significantly impacting the prognosis of liver transplantation and other liver surgeries. Betaine-homocysteine methyltransferase (BHMT), a crucial enzyme in the methionine cycle, has been previously confirmed the pivotal role in hepatocellular carcinoma, and it has also been demonstrated that BHMT inhibits inflammation, apoptosis, but its role in liver IR injury remains unknow. Following I/R injury, we found that BHMT expression was significantly upregulated in human liver transplant specimens, mice and hepatocytes. Utilizing BHMT knockout mice, we established an in vivo model of liver IR injury, and with BHMT knockout and overexpression AML12 cell lines, we created an in vitro hypoxia-reoxygenation model. Our findings reveal that BHMT deficiency exacerbates liver IR injury, leading to increased reactive oxygen species, apoptosis and inflammation, whereas BHMT overexpression mitigates these effects. We observed that BHMT inhibits the c-Jun N-terminal kinase (JNK)/p38 signaling pathway in liver IR injury by interacting with TAK1 and inhibiting its activity. The application of 5z-7-ox, a TAK1 inhibitor, reversed the worsening of liver IR injury and the activation of the JNK/p38 pathway associated with BHMT deficiency. These results demonstrate that BHMT protects against liver IR injury by targeting TAK1 and inhibiting the JNK/p38 signaling pathway. Our findings suggest that BHMT may be a promising therapeutic target for preventing liver IR injury.
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Affiliation(s)
- Xudong Liu
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Henan Key Laboratory of Digestive Organ Transplantation, Zhengzhou, China
- Open and Key Laboratory of Hepatobiliary & Pancreatic Surgery and Digestive Organ Transplantation at Henan Province, Zhengzhou, China
| | - Jihua Shi
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Henan Key Laboratory of Digestive Organ Transplantation, Zhengzhou, China
- Open and Key Laboratory of Hepatobiliary & Pancreatic Surgery and Digestive Organ Transplantation at Henan Province, Zhengzhou, China
| | - Min Wu
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Henan Key Laboratory of Digestive Organ Transplantation, Zhengzhou, China
- Open and Key Laboratory of Hepatobiliary & Pancreatic Surgery and Digestive Organ Transplantation at Henan Province, Zhengzhou, China
| | - Jie Gao
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Henan Key Laboratory of Digestive Organ Transplantation, Zhengzhou, China
- Open and Key Laboratory of Hepatobiliary & Pancreatic Surgery and Digestive Organ Transplantation at Henan Province, Zhengzhou, China
| | - Yi Zhang
- Department of Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Wenzhi Guo
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Henan Key Laboratory of Digestive Organ Transplantation, Zhengzhou, China
- Open and Key Laboratory of Hepatobiliary & Pancreatic Surgery and Digestive Organ Transplantation at Henan Province, Zhengzhou, China
| | - Shuijun Zhang
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Henan Key Laboratory of Digestive Organ Transplantation, Zhengzhou, China
- Open and Key Laboratory of Hepatobiliary & Pancreatic Surgery and Digestive Organ Transplantation at Henan Province, Zhengzhou, China
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Yang L, Zhu L, Qi B, Zhang Y, Ni C, Zhang Y, Shi X, Xia Q, Masters J, Ma D, Yu W. Dexmedetomidine use during orthotopic liver transplantation surgery on early allograft dysfunction: a randomized controlled trial. Int J Surg 2024; 110:5518-5526. [PMID: 38768468 PMCID: PMC11392095 DOI: 10.1097/js9.0000000000001669] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2024] [Accepted: 05/09/2024] [Indexed: 05/22/2024]
Abstract
BACKGROUND Previous studies have shown a protective effect of dexmedetomidine use in kidney transplantation. In contrast, it is not known whether intraoperative administration of dexmedetomidine can reduce early allograft dysfunction (EAD) incidence following liver transplantation. OBJECTIVE To investigate the effect of dexmedetomidine use during surgery on EAD following orthotopic liver transplantation (OLT). STUDY DESIGN This is a single-center, double-blinded, placebo-controlled randomized clinical trial. Three hundred thirty adult patients undergoing OLT were enrolled from 14th January 2019 to 22nd May 2022. Patients received dexmedetomidine or normal saline during surgery. One year follow-ups were recorded. METHODS Patients were randomized to two groups receiving either dexmedetomidine or normal saline intraoperatively. For patients in the dexmedetomidine group, a loading dose (1 μg/kg over 10 min) of dexmedetomidine was given after induction of anesthesia followed by a continuous infusion (0.5 μg/kg /h) until the end of surgery. For patients in the normal saline group, an equal volume loading dose of 0.9% saline was given after the induction of anesthesia followed by an equal volume continuous infusion until the end of surgery. The primary outcome was EAD. Secondary outcomes included primary graft nonfunction, acute kidney injury, and acute lung injury/acute respiratory distress syndrome. RESULTS Of 330 patients included in the intention-to-treat analysis, 165 were in the dexmedetomidine group [mean (SD) age, 49 (10) years; 117 (70.9%) men], and 165 were in the normal saline group [mean SD age, 49 (9) years; 118 (74%) men]. 39 (24.4%) patients in the dexmedetomidine group and 31 (19.4%) in normal saline group developed EAD and the difference was statistically insignificant ( P =0.28). Secondary outcomes including primary graft nonfunction and acute kidney injury was similar between the two groups. CONCLUSION Intraoperative administration of dexmedetomidine did not reduce EAD rate after OLT.
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Affiliation(s)
- Liqun Yang
- Department of Anesthesiology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai; Key Laboratory of Anesthesiology (Shanghai Jiao Tong University), Ministry of Education
| | - Ling Zhu
- Department of Anesthesiology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai; Key Laboratory of Anesthesiology (Shanghai Jiao Tong University), Ministry of Education
| | - Bo Qi
- Department of Anesthesiology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai; Key Laboratory of Anesthesiology (Shanghai Jiao Tong University), Ministry of Education
| | - Yin Zhang
- Department of Anesthesiology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai; Key Laboratory of Anesthesiology (Shanghai Jiao Tong University), Ministry of Education
| | - Chenlu Ni
- Department of Anesthesiology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai; Key Laboratory of Anesthesiology (Shanghai Jiao Tong University), Ministry of Education
| | - Yijue Zhang
- Department of Anesthesiology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai; Key Laboratory of Anesthesiology (Shanghai Jiao Tong University), Ministry of Education
| | - Xiao Shi
- Department of Anesthesiology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai; Key Laboratory of Anesthesiology (Shanghai Jiao Tong University), Ministry of Education
| | - Qiang Xia
- Department of Hepatology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China
| | - Joe Masters
- Division of Anesthetics, Pain Medicine & Intensive Care, Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, Chelsea and Westminster Hospital, London, United Kingdom
| | - Daqing Ma
- Division of Anesthetics, Pain Medicine & Intensive Care, Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, Chelsea and Westminster Hospital, London, United Kingdom
- Perioperative and Systems Medicine Laboratory, Children’s Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, China
| | - Weifeng Yu
- Department of Anesthesiology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai; Key Laboratory of Anesthesiology (Shanghai Jiao Tong University), Ministry of Education
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Zhao T, Zhong G, Wang Y, Cao R, Song S, Li Y, Wan G, Sun H, Huang M, Bi H, Jiang Y. Pregnane X Receptor Activation in Liver Macrophages Protects against Endotoxin-Induced Liver Injury. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2024; 11:e2308771. [PMID: 38477509 PMCID: PMC11109625 DOI: 10.1002/advs.202308771] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/15/2023] [Revised: 02/24/2024] [Indexed: 03/14/2024]
Abstract
Endotoxemia-related acute liver injury has a poor prognosis and high mortality, and macrophage polarization plays a central role in the pathological process. Pregnane X receptor (PXR) serves as a nuclear receptor and xenosensor, safeguarding the liver from toxic stimuli. However, the effect and underlying mechanism of PXR activation on endotoxemic liver injury remain largely unknown. Here, the expression of PXR is reported in human and murine macrophages, and PXR activation modified immunotypes of macrophages. Moreover, PXR activation significantly attenuated endotoxemic liver injury and promoted macrophage M2 polarization. Macrophage depletion by GdCl3 confirmed the essential of macrophages in the beneficial effects observed with PXR activation. The role of PXR in macrophages is further validated using AAV8-F4/80-Pxr shRNA-treated mice; the PXR-mediated hepatoprotection is impaired, and M2 polarization enhancement is blunted. Additionally, treatment with PXR agonists inhibited lipopolysaccharide (LPS)-induced M1 polarization and favored M2 polarization in BMDM, Raw264.7, and THP-1 cells. Further analyses revealed an interaction between PXR and p-STAT6 in vivo and in vitro. Moreover, blocking Pxr or Stat6 abolished the PXR-induced polarization shift. Collectively, macrophage PXR activation attenuated endotoxin-induced liver injury and regulated macrophage polarization through the STAT6 signaling pathway, which provided a potential therapeutic target for managing endotoxemic liver injury.
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Affiliation(s)
- Tingting Zhao
- Guangdong Provincial Key Laboratory of New Drug Design and EvaluationSchool of Pharmaceutical SciencesSun Yat‐Sen UniversityGuangzhou510006China
- Institute of Clinical PharmacologySun Yat‐Sen UniversityGuangzhou510006China
| | - Guoping Zhong
- Guangdong Provincial Key Laboratory of New Drug Design and EvaluationSchool of Pharmaceutical SciencesSun Yat‐Sen UniversityGuangzhou510006China
- Institute of Clinical PharmacologySun Yat‐Sen UniversityGuangzhou510006China
| | - Ying Wang
- Sun Yat‐Sen Memorial HospitalSun Yat‐Sen UniversityGuangzhou510006China
| | - Renjie Cao
- Guangdong Provincial Key Laboratory of New Drug Design and EvaluationSchool of Pharmaceutical SciencesSun Yat‐Sen UniversityGuangzhou510006China
- Institute of Clinical PharmacologySun Yat‐Sen UniversityGuangzhou510006China
| | - Shaofei Song
- Guangdong Provincial Key Laboratory of New Drug Design and EvaluationSchool of Pharmaceutical SciencesSun Yat‐Sen UniversityGuangzhou510006China
- Institute of Clinical PharmacologySun Yat‐Sen UniversityGuangzhou510006China
| | - Yuan Li
- Guangdong Provincial Key Laboratory of New Drug Design and EvaluationSchool of Pharmaceutical SciencesSun Yat‐Sen UniversityGuangzhou510006China
- Institute of Clinical PharmacologySun Yat‐Sen UniversityGuangzhou510006China
| | - Guohui Wan
- Guangdong Provincial Key Laboratory of New Drug Design and EvaluationSchool of Pharmaceutical SciencesSun Yat‐Sen UniversityGuangzhou510006China
- Institute of Clinical PharmacologySun Yat‐Sen UniversityGuangzhou510006China
| | - Haiyan Sun
- School of Food and DrugShenzhen Polytechnic UniversityShenzhen518055China
| | - Min Huang
- Guangdong Provincial Key Laboratory of New Drug Design and EvaluationSchool of Pharmaceutical SciencesSun Yat‐Sen UniversityGuangzhou510006China
- Institute of Clinical PharmacologySun Yat‐Sen UniversityGuangzhou510006China
| | - Huichang Bi
- NMPA Key Laboratory for Research and Evaluation of Drug Metabolism & Guangdong Provincial Key Laboratory of New Drug ScreeningSchool of Pharmaceutical SciencesSouthern Medical UniversityGuangzhou510006China
| | - Yiming Jiang
- Guangdong Provincial Key Laboratory of New Drug Design and EvaluationSchool of Pharmaceutical SciencesSun Yat‐Sen UniversityGuangzhou510006China
- Institute of Clinical PharmacologySun Yat‐Sen UniversityGuangzhou510006China
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Fang G, Liu S, Liu B. Preventive and therapeutic effects of rifaximin on hepatic encephalopathy with differential application dosages and strategies: a network meta-analysis. BMC Gastroenterol 2024; 24:94. [PMID: 38439005 PMCID: PMC10910798 DOI: 10.1186/s12876-024-03184-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/26/2023] [Accepted: 02/20/2024] [Indexed: 03/06/2024] Open
Abstract
BACKGROUND Hepatic encephalopathy (HE) is a neuropsychiatric syndrome that affects the prognosis of patients with liver disease and is considered an independent risk factor for hospitalization and death. Rifaximin has been approved for HE treatment. This review will analyze the effect of rifaximin on different stages of HE with differential application dosages and strategies by traditional and network meta-analyses. METHODS We performed a systematic search of PubMed, EmBase, and Cochrane Library databases up to February 26, 2023, to identify randomized controlled trials (RCTs) about rifaximin for the prevention and treatment of HE. The outcomes included incidence of HE and HE progression, HE reversal, mortality, and adverse effects. RESULTS A total of 21 studies were included. In the primary prevention of HE, rifaximin significantly reduced the incidence of HE (OR: 0.66; 95% CI: 0.45, 0.96; p = 0.032). In secondary prevention, rifaximin significantly reduced the risk of recurrence in patients who were in remission (OR: 0.38; 95% CI: 0.28, 0.52; p < 0.001). In the treatment of minimal HE, rifaximin significantly reduced the breakthrough of MHE to OHE (OR: 0.17; 95% CI: 0.04,0.63; p = 0.008). Rifaximin also significantly improved the clinical symptoms of MHE and OHE patients (OR: 3.76; 95% CI: 2.69, 5.25; p < 0.001). However, rifaximin did not reduce mortality at any stage in HE patients (OR: 0.79; 95% CI: 0.58, 1.08; p = 0.133). Additionally, rifaximin did not increase the risk of adverse effects (OR: 0.96; 95% CI: 0.74, 1.24; p = 0.749). In the network meta-analysis, the 400 mg T.I.D. intervention had a relative advantage for HE risks in primary and secondary prevention. In the treatment of MHE, 600 mg b.i.d. was superior in preventing the breakthrough from MHE to OHE. CONCLUSION Rifaximin prevented HE risks and progression and improved clinical symptoms in patients with MHE but did not reduce mortality. For primary and secondary prevention, 400 mg t.i.d. could be considered. 600 mg b.i.d. could be considered in patients with MHE.
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Affiliation(s)
- Guihua Fang
- Department of Infectious Diseases, The Affiliated Hospital of Guangdong Medical University, No.57 Renmin Avenue South, 524000, Xiashan, Zhanjiang, Guangdong, China
| | - Shuna Liu
- Department of Infectious Diseases, The Affiliated Hospital of Guangdong Medical University, No.57 Renmin Avenue South, 524000, Xiashan, Zhanjiang, Guangdong, China
| | - Bin Liu
- Laboratory of Hepatobiliary Surgery, The Affiliated Hospital of Guangdong Medical University, 524000, Zhanjiang, Guangdong, China.
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DuPont HL. The potential for development of clinically relevant microbial resistance to rifaximin-α: a narrative review. Clin Microbiol Rev 2023; 36:e0003923. [PMID: 37971270 PMCID: PMC10732030 DOI: 10.1128/cmr.00039-23] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2023] Open
Abstract
Rifaximin-α is a gut-targeted antibiotic indicated for numerous gastrointestinal and liver diseases. Its multifaceted mechanism of action goes beyond direct antimicrobial effects, including alterations in bacterial virulence, cytoprotective effects on host epithelial cells, improvement of impaired intestinal permeability, and reduction of proinflammatory cytokine expression via activation of the pregnane X receptor. Rifaximin-α is virtually non-absorbed, with low systemic drug levels contributing to its excellent safety profile. While there are high concentrations of drug in the colon, low water solubility leads to low colonic drug bioavailability, protecting the gut microbiome. Rifaximin-α appears to be more active in the bile-rich small bowel. Its important biologic effects are largely at sub-inhibitory concentration. Although in vitro testing of clinical isolates from rifaximin recipients has revealed rifaximin-resistant strains in some studies, the risk of emergent rifaximin-α resistance appears to be lower than for many other antibiotics. Rifaximin-α has been used for many years for traveler's diarrhea with no apparent increase in resistance levels in causative pathogens. Further, rifaximin-α retains its efficacy after long-term and recurrent usage in chronic gastrointestinal disorders. There are numerous reasons why the risk of microbial resistance to rifaximin-α may be lower than that for other agents, including low intestinal bioavailability in the aqueous colon, the mechanisms of action of rifaximin-α not requiring inhibitory concentrations of drug, and the low risk of cross transmission of rifaximin-α resistance between bacterial species. Reported emergence of vancomycin-resistant Enterococcus in liver-disease patients maintained on rifaximin needs to be actively studied. Further studies are required to assess the possible correlation between in vitro resistance and rifaximin-α efficacy.
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Affiliation(s)
- Herbert L. DuPont
- School of Public Health and McGovern Medical School, Baylor College of Medicine, Kelsey Research Foundation, University of Texas Health Science Center Houston, Houston, Texas, USA
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Parisse S, Lai Q, Martini F, Martini A, Ferri F, Mischitelli M, Melandro F, Mennini G, Rossi M, Alvaro D, Ginanni Corradini S. Rifaximin Reduces Risk of All-Cause Hospitalization in Cirrhotic Liver Transplant Candidates with Hepatic Encephalopathy. J Clin Med 2023; 12:6871. [PMID: 37959336 PMCID: PMC10647372 DOI: 10.3390/jcm12216871] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2023] [Revised: 10/25/2023] [Accepted: 10/30/2023] [Indexed: 11/15/2023] Open
Abstract
UNLABELLED In cirrhotic patients listed for liver transplantation (LT) with a history of hepatic encephalopathy (HE), rifaximin reduces the number of hospitalizations, but whether it influences the time to first hospitalization is unknown. AIMS to evaluate the time-dependent impact of rifaximin on the risk of all-cause hospitalization and dropout in patients on the LT waiting list. METHODS Consecutive patients listed for LT were retrospectively enrolled. After balancing populations with and without rifaximin treatment using the inverse probability therapy weighting analysis, Fine-Gray multivariable competing risk analyses were run to explore risk factors for the first episode of hospitalization and dropout. RESULTS When comparing 92 patients taking rifaximin to the untreated group of 152, rifaximin treatment was not associated with any of the study outcomes. In the subset of patients with a history of HE at waitlist entry (N = 81 rifaximin-treated and N = 39 untreated), rifaximin intake was independently associated with a lower risk of hospitalization for all causes (SHR 0.638; 95.0% CI 0.418-0.973; p = 0.037) and for HE (SHR 0.379; 95.0% CI 0.207-0.693; p = 0.002). CONCLUSIONS cirrhotic LT candidates with a prior history of HE rifaximin treatment are associated with a lower risk of time-dependent all-cause hospitalization, likely due to its unique effect on gut microbiome composition/function.
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Affiliation(s)
- Simona Parisse
- Department of Translational and Precision Medicine, “Sapienza” University of Rome, Viale dell’Università 37, 00185 Rome, Italy; (S.P.); (F.M.); (A.M.); (F.F.); (M.M.); (D.A.)
| | - Quirino Lai
- General Surgery and Organ Transplantation Unit, “Sapienza” University of Rome, Viale del Policlinico 155, 00161 Rome, Italy; (Q.L.); (F.M.); (G.M.); (M.R.)
| | - Francesca Martini
- Department of Translational and Precision Medicine, “Sapienza” University of Rome, Viale dell’Università 37, 00185 Rome, Italy; (S.P.); (F.M.); (A.M.); (F.F.); (M.M.); (D.A.)
| | - Alice Martini
- Department of Translational and Precision Medicine, “Sapienza” University of Rome, Viale dell’Università 37, 00185 Rome, Italy; (S.P.); (F.M.); (A.M.); (F.F.); (M.M.); (D.A.)
| | - Flaminia Ferri
- Department of Translational and Precision Medicine, “Sapienza” University of Rome, Viale dell’Università 37, 00185 Rome, Italy; (S.P.); (F.M.); (A.M.); (F.F.); (M.M.); (D.A.)
| | - Monica Mischitelli
- Department of Translational and Precision Medicine, “Sapienza” University of Rome, Viale dell’Università 37, 00185 Rome, Italy; (S.P.); (F.M.); (A.M.); (F.F.); (M.M.); (D.A.)
| | - Fabio Melandro
- General Surgery and Organ Transplantation Unit, “Sapienza” University of Rome, Viale del Policlinico 155, 00161 Rome, Italy; (Q.L.); (F.M.); (G.M.); (M.R.)
| | - Gianluca Mennini
- General Surgery and Organ Transplantation Unit, “Sapienza” University of Rome, Viale del Policlinico 155, 00161 Rome, Italy; (Q.L.); (F.M.); (G.M.); (M.R.)
| | - Massimo Rossi
- General Surgery and Organ Transplantation Unit, “Sapienza” University of Rome, Viale del Policlinico 155, 00161 Rome, Italy; (Q.L.); (F.M.); (G.M.); (M.R.)
| | - Domenico Alvaro
- Department of Translational and Precision Medicine, “Sapienza” University of Rome, Viale dell’Università 37, 00185 Rome, Italy; (S.P.); (F.M.); (A.M.); (F.F.); (M.M.); (D.A.)
| | - Stefano Ginanni Corradini
- Department of Translational and Precision Medicine, “Sapienza” University of Rome, Viale dell’Università 37, 00185 Rome, Italy; (S.P.); (F.M.); (A.M.); (F.F.); (M.M.); (D.A.)
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Parente A, Flores Carvalho M, Eden J, Dutkowski P, Schlegel A. Mitochondria and Cancer Recurrence after Liver Transplantation-What Is the Benefit of Machine Perfusion? Int J Mol Sci 2022; 23:9747. [PMID: 36077144 PMCID: PMC9456431 DOI: 10.3390/ijms23179747] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2022] [Revised: 08/23/2022] [Accepted: 08/24/2022] [Indexed: 11/16/2022] Open
Abstract
Tumor recurrence after liver transplantation has been linked to multiple factors, including the recipient's tumor burden, donor factors, and ischemia-reperfusion injury (IRI). The increasing number of livers accepted from extended criteria donors has forced the transplant community to push the development of dynamic perfusion strategies. The reason behind this progress is the urgent need to reduce the clinical consequences of IRI. Two concepts appear most beneficial and include either the avoidance of ischemia, e.g., the replacement of cold storage by machine perfusion, or secondly, an endischemic organ improvement through perfusion in the recipient center prior to implantation. While several concepts, including normothermic perfusion, were found to reduce recipient transaminase levels and early allograft dysfunction, hypothermic oxygenated perfusion also reduced IRI-associated post-transplant complications and costs. With the impact on mitochondrial injury and subsequent less IRI-inflammation, this endischemic perfusion was also found to reduce the recurrence of hepatocellular carcinoma after liver transplantation. Firstly, this article highlights the contributing factors to tumor recurrence, including the surgical and medical tissue trauma and underlying mechanisms of IRI-associated inflammation. Secondly, it focuses on the role of mitochondria and associated interventions to reduce cancer recurrence. Finally, the role of machine perfusion technology as a delivery tool and as an individual treatment is discussed together with the currently available clinical studies.
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Affiliation(s)
- Alessandro Parente
- The Liver Unit, Queen Elizabeth University Hospital Birmingham, Birmingham B15 2GW, UK
| | - Mauricio Flores Carvalho
- Fondazione IRCCS Ca’ Granda, Ospedale Maggiore Policlinico, Centre of Preclinical Research, 20122 Milan, Italy
| | - Janina Eden
- Department of Surgery and Transplantation, Swiss HPB Centre, University Hospital Zurich, 8091 Zurich, Switzerland
| | - Philipp Dutkowski
- Department of Surgery and Transplantation, Swiss HPB Centre, University Hospital Zurich, 8091 Zurich, Switzerland
| | - Andrea Schlegel
- Fondazione IRCCS Ca’ Granda, Ospedale Maggiore Policlinico, Centre of Preclinical Research, 20122 Milan, Italy
- Department of Surgery and Transplantation, Swiss HPB Centre, University Hospital Zurich, 8091 Zurich, Switzerland
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9
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Zhang L, Cui LL, Yang WH, Xue FS, Zhu ZJ. Effect of intraoperative dexmedetomidine on hepatic ischemia-reperfusion injury in pediatric living-related liver transplantation: A propensity score matching analysis. Front Surg 2022; 9:939223. [PMID: 35965870 PMCID: PMC9365069 DOI: 10.3389/fsurg.2022.939223] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2022] [Accepted: 07/13/2022] [Indexed: 11/13/2022] Open
Abstract
BackgroundHepatic ischemia-reperfusion injury (HIRI) is largely unavoidable during liver transplantation (LT). Dexmedetomidine (DEX), an α2-adrenergic agonist, exerts a variety of organ-protective effects in pediatric populations. However, evidence remains relatively limited about its hepatoprotective effects in pediatric living-related LT.MethodsA total of 121 pediatric patients undergoing living-related LT from June 2015 to December 2018 in our hospital were enrolled. They were classified into DEX or non-DEX groups according to whether an infusion of DEX was initiated from incision to the end of surgery. Primary outcomes were postoperative liver graft function and the severity of HIRI. Multivariate logistic regression and propensity score matching (PSM) analyses were performed to identify any association.ResultsA 1:1 matching yielded 35 well-balanced pairs. Before matching, no significant difference was found in baseline characteristics between groups except for warm ischemia time, which was longer in the non-DEX group (44 [38–50] vs. 40 [37–44] min, p = 0.017). After matching, the postoperative peak lactic dehydrogenase levels decreased significantly in the DEX group than in the non-DEX group (622 [516–909] vs. 970 [648–1,490] IU/L, p = 0.002). Although there was no statistical significance, a tendency toward a decrease in moderate-to-extreme HIRI rate was noted in the DEX group compared to the non-DEX group (68.6% vs. 82.9%, p = 0.163). Patients in the DEX group also received a significantly larger dosage of epinephrine as postreperfusion syndrome (PRS) treatment (0.28 [0.17–0.32] vs. 0.17 [0.06–0.30] µg/kg, p = 0.010). However, there were no significant differences between groups in PRS and acute kidney injury incidences, mechanical ventilation duration, intensive care unit, and hospital lengths of stay. Multivariate analysis revealed a larger graft-to-recipient weight ratio (odds ratio [OR] 2.657, 95% confidence interval [CI], 1.132–6.239, p = 0.025) and intraoperative DEX administration (OR 0.333, 95% CI, 0.130–0.851, p = 0.022) to be independent predictors of moderate-to-extreme HIRI.ConclusionThis study demonstrated that intraoperative DEX could potentially decrease the risk of HIRI but was associated with a significant increase in epinephrine requirement for PRS in pediatric living-related LT. Further studies, including randomized controlled studies, are warranted to provide more robust evidence.
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Affiliation(s)
- Liang Zhang
- Department of Anesthesiology, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Ling-Li Cui
- Department of Anesthesiology, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Wen-He Yang
- Department of Anesthesiology, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Fu-Shan Xue
- Department of Anesthesiology, Beijing Friendship Hospital, Capital Medical University, Beijing, China
- Correspondence: Fu-Shan Xue Zhu-Jun Zhu
| | - Zhi-Jun Zhu
- Division of Liver Transplantation, Department of General Surgery, Beijing Friendship Hospital, Capital Medical University, Beijing, China
- Clinical Center for Pediatric Liver Transplantation, Capital Medical University, Beijing, China
- Liver Transplantation Center, National Clinical Research Center for Digestive Diseases, Beijing, China
- Correspondence: Fu-Shan Xue Zhu-Jun Zhu
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10
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Kaltenmeier C, Wang R, Popp B, Geller D, Tohme S, Yazdani HO. Role of Immuno-Inflammatory Signals in Liver Ischemia-Reperfusion Injury. Cells 2022; 11:cells11142222. [PMID: 35883665 PMCID: PMC9323912 DOI: 10.3390/cells11142222] [Citation(s) in RCA: 61] [Impact Index Per Article: 20.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2022] [Revised: 07/09/2022] [Accepted: 07/13/2022] [Indexed: 02/01/2023] Open
Abstract
Ischemia reperfusion injury (IRI) is a major obstacle in liver resection and liver transplantation. The initial step of IRI is mediated through ischemia which promotes the production of reactive oxygen species in Kupffer cells. This furthermore promotes the activation of pro-inflammatory signaling cascades, including tumor necrosis factor-alpha, IL-6, interferon, inducible nitric oxide synthase, TLR9/nuclear-factor kappa B pathway, and the production of damage-associated molecular patterns (DAMPs), such as ATP, histone, high mobility group box 1 (HMGB1), urate, mitochondrial formyl peptides and S100 proteins. With ongoing cell death of hepatocytes during the ischemic phase, DAMPs are built up and released into the circulation upon reperfusion. This promotes a cytokines/chemokine storm that attracts neutrophils and other immune cells to the site of tissue injury. The effect of IRI is further aggravated by the release of cytokines and chemokines, such as epithelial neutrophil activating protein (CXCL5), KC (CXCL1) and MIP-2 (CXCL2), the complement proteins C3a and C5a, mitochondrial-derived formyl peptides, leukotriene B4 and neutrophil extracellular traps (NETs) from migrating neutrophils. These NETs can also activate platelets and form Neutrophil-platelet microthrombi to further worsen ischemia in the liver. In this review we aim to summarize the current knowledge of mediators that promote liver IRI, and we will discuss the role of neutrophils and neutrophil extracellular traps in mediating IRI.
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Affiliation(s)
- Christof Kaltenmeier
- Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, PA 15213, USA; (C.K.); (R.W.); (D.G.); (S.T.)
| | - Ronghua Wang
- Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, PA 15213, USA; (C.K.); (R.W.); (D.G.); (S.T.)
| | - Brandon Popp
- Lake Erie College of Osteopathic Medicine, Erie, PA 16509, USA;
| | - David Geller
- Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, PA 15213, USA; (C.K.); (R.W.); (D.G.); (S.T.)
| | - Samer Tohme
- Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, PA 15213, USA; (C.K.); (R.W.); (D.G.); (S.T.)
| | - Hamza O. Yazdani
- Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, PA 15213, USA; (C.K.); (R.W.); (D.G.); (S.T.)
- Correspondence:
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11
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Binda C, Gibiino G, Coluccio C, Sbrancia M, Dajti E, Sinagra E, Capurso G, Sambri V, Cucchetti A, Ercolani G, Fabbri C. Biliary Diseases from the Microbiome Perspective: How Microorganisms Could Change the Approach to Benign and Malignant Diseases. Microorganisms 2022; 10:312. [PMID: 35208765 PMCID: PMC8877314 DOI: 10.3390/microorganisms10020312] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2021] [Revised: 01/23/2022] [Accepted: 01/24/2022] [Indexed: 11/18/2022] Open
Abstract
Recent evidence regarding microbiota is modifying the cornerstones on pathogenesis and the approaches to several gastrointestinal diseases, including biliary diseases. The burden of biliary diseases, indeed, is progressively increasing, considering that gallstone disease affects up to 20% of the European population. At the same time, neoplasms of the biliary system have an increasing incidence and poor prognosis. Framing the specific state of biliary eubiosis or dysbiosis is made difficult by the use of heterogeneous techniques and the sometimes unwarranted invasive sampling in healthy subjects. The influence of the microbial balance on the health status of the biliary tract could also account for some of the complications surrounding the post-liver-transplant phase. The aim of this extensive narrative review is to summarize the current evidence on this topic, to highlight gaps in the available evidence in order to guide further clinical research in these settings, and, eventually, to provide new tools to treat biliary lithiasis, biliopancreatic cancers, and even cholestatic disease.
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Affiliation(s)
- Cecilia Binda
- Gastroenterology and Digestive Endoscopy Unit, Forlì-Cesena Hospitals, Ausl Romagna, 47121 Forlì, Italy; (C.B.); (G.G.); (M.S.); (E.D.); (C.F.)
| | - Giulia Gibiino
- Gastroenterology and Digestive Endoscopy Unit, Forlì-Cesena Hospitals, Ausl Romagna, 47121 Forlì, Italy; (C.B.); (G.G.); (M.S.); (E.D.); (C.F.)
| | - Chiara Coluccio
- Gastroenterology and Digestive Endoscopy Unit, Forlì-Cesena Hospitals, Ausl Romagna, 47121 Forlì, Italy; (C.B.); (G.G.); (M.S.); (E.D.); (C.F.)
| | - Monica Sbrancia
- Gastroenterology and Digestive Endoscopy Unit, Forlì-Cesena Hospitals, Ausl Romagna, 47121 Forlì, Italy; (C.B.); (G.G.); (M.S.); (E.D.); (C.F.)
| | - Elton Dajti
- Gastroenterology and Digestive Endoscopy Unit, Forlì-Cesena Hospitals, Ausl Romagna, 47121 Forlì, Italy; (C.B.); (G.G.); (M.S.); (E.D.); (C.F.)
- Department of Medical and Surgical Sciences–DIMEC, Alma Mater Studiorum–University of Bologna, 90015 Bologna, Italy; (A.C.); (G.E.)
| | - Emanuele Sinagra
- Endoscopy Unit, Fondazione Istituto San Raffaele-G. Giglio, 90015 Cefalù, Italy;
- Euro-Mediterranean Institute of Science and Technology (IEMEST), 90100 Palermo, Italy
| | - Gabriele Capurso
- Division of Pancreato-Biliary Endoscopy and EUS, Pancreas Translational and Clinical Research Center, San Raffaele Scientific Institute IRCCS, 20132 Milano, Italy;
| | - Vittorio Sambri
- Unit of Microbiology, The Great Romagna Hub Laboratory, 47522 Pievesestina, Italy;
- Unit of Microbiology, Department of Pathological Anatomy, Trasfusion Medicine and Laboratory Medicine, University of Bologna, 40125 Bologna, Italy
| | - Alessandro Cucchetti
- Department of Medical and Surgical Sciences–DIMEC, Alma Mater Studiorum–University of Bologna, 90015 Bologna, Italy; (A.C.); (G.E.)
- Department of General and Oncologic Surgery, Morgagni-Pierantoni Hospital, Ausl Romagna, 47121 Forlì, Italy
| | - Giorgio Ercolani
- Department of Medical and Surgical Sciences–DIMEC, Alma Mater Studiorum–University of Bologna, 90015 Bologna, Italy; (A.C.); (G.E.)
- Department of General and Oncologic Surgery, Morgagni-Pierantoni Hospital, Ausl Romagna, 47121 Forlì, Italy
| | - Carlo Fabbri
- Gastroenterology and Digestive Endoscopy Unit, Forlì-Cesena Hospitals, Ausl Romagna, 47121 Forlì, Italy; (C.B.); (G.G.); (M.S.); (E.D.); (C.F.)
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Yu X, Jin Y, Zhou W, Xiao T, Wu Z, Su J, Gao H, Shen P, Zheng B, Luo Q, Li L, Xiao Y. Rifaximin Modulates the Gut Microbiota to Prevent Hepatic Encephalopathy in Liver Cirrhosis Without Impacting the Resistome. Front Cell Infect Microbiol 2022; 11:761192. [PMID: 35118004 PMCID: PMC8804384 DOI: 10.3389/fcimb.2021.761192] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2021] [Accepted: 12/22/2021] [Indexed: 12/21/2022] Open
Abstract
The gut microbiota has an important role in the pathogenesis of hepatic encephalopathy(HE). Rifaximin, an intestinal non-absorbable antibacterial agent, is effective in the treatment of HE. However, whether long-term prophylactic use induces antibacterial resistance and its mechanism for treating HE remains unclear. This prospective study assessed the impact of 12 weeks rifaximin administration on the gut microbiota and resistome in cirrhotic patients. Fecal sampling was conducted 1 day before the first rifaximin administration and at Weeks 1, 2, 4, 6, 8, 10, 12 of the study. Thirty cirrhotic patients who were in remission from recurrent HE was enrolled to receive rifaximin (400mg TID for 12 weeks). Rifaximin improved hyperammonemia and cognitive function in the 21 patients who completed rifaximin treatment. The dynamic observations showed the gut microbiota diversity, composition and the number of resistance genes, plasmids, insertion sequences did not change significantly during the period(P>0.05). Metabolic pathways such as aromatic amino acids, tryptophan synthesis, urea cycle, and LPS synthesis reduced. No new antimicrobial resistance genes was emergenced. However, the number of aminoglycosides, rifamycin and phenolic resistance genes increased, whereas tetracycline, fosfomycin and cephamycin decreased (P<0.05). Changes in the abundance of E. coli, K. pneumoniae, and B. longum strains correlated with changes of resistance genes. Prophylactic use of rifaximin for 12 weeks improved hyperammonemia and neurophysiological function, maintained gut microbiota diversity, composition and did not change the overall resistome. Rifaximin altered expression of HE-related metabolic pathways. All of these effects could play a key role in preventing HE. Clinical Trial Registration: ChiCTR1900022234 (registered at the Chinese Clinical Trial Registry).
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Affiliation(s)
- Xiao Yu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
- Department of Respiratory and Critical Care Medicine, First Hospital of Shanxi Medical University, Taiyuan, China
| | - Ye Jin
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Wangxiao Zhou
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Tingting Xiao
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Zhongwen Wu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Junwei Su
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Hainv Gao
- Department of Infectious Disease, ShuLan (Hangzhou) Hospital Affiliated to Zhejiang Shuren University Shulan International Medical College, Hangzhou, China
| | - Ping Shen
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Beiwen Zheng
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Qixia Luo
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Lanjuan Li
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Yonghong Xiao
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
- *Correspondence: Yonghong Xiao,
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13
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Hou W, Wei B, Liu HS. The Protective Effect of Panax notoginseng Mixture on Hepatic Ischemia/Reperfusion Injury in Mice via Regulating NR3C2, SRC, and GAPDH. Front Pharmacol 2021; 12:756259. [PMID: 34858181 PMCID: PMC8632037 DOI: 10.3389/fphar.2021.756259] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2021] [Accepted: 10/13/2021] [Indexed: 11/13/2022] Open
Abstract
Panax notoginseng mixture (PNM) has the characteristics of multicomponent, multitarget, and multieffect, which can cope with the multidirectional and multidimensional complex pathological process caused by hepatic ischemia/reperfusion injury (HIRI). Our animal experiments showed that PNM composed of notoginseng, dogwood, and white peony root could significantly reduce the level of aspartate transaminase and alanine aminotransferase in the blood of mice with HIRI, indicating that this preparation had a protective effect on HIRI in mice. Therefore, on this basis, the molecular mechanism of PNM intervention in HIRI was further explored by network pharmacology. First, target genes corresponding to active components and HIRI were obtained through databases such as TCMSP, Pharm Mapper, Swiss Target Prediction, GeneCards, and so on. All target genes were standardized by Uniprot database, and a total of 291 target genes with their intersection were obtained. Then, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways and biological processes (BPs) of 291 target genes were obtained through the online public platform of DAVID. A total of 177 KEGG pathways and 337 BPs were obtained by setting p < 0.01 and false discovery rate <0.05. The network mapping map of components and disease targets was drawn by Cytoscape, and the top 10 Hub target genes related to HIRI were obtained. At the same time, the String database was used to obtain the protein-protein interaction dataset, which was imported into Cytoscape, and the first 10 Hub target genes were obtained. The Hub target genes obtained by the above two methods were molecular docking with their corresponding small molecule compounds through DockThor online tool. The results showed that the docking of paeoniflorin with glyceraldehyde 3-phosphate dehydrogenase (GAPDH), paeoniflorin and loganin with SRC, ginsenoside Rb1 with NR3C2, ursolic acid and oleanolic acid with IL-6, paeoniflorin docking VEGFA, and MMP9. Finally, NR3C2, SRC, and GAPDH were identified as target genes in this study by referring to relevant literature reports. After verification by immunohistochemical experiments, compared with the sham group, the above three target genes were highly expressed in the HIRI group (p < 0.01). Compared with the HIRI group, the expression of three target genes in the PNM + HIRI group was significantly decreased (p < 0.01). The results showed that PNM could protect mouse HIRI by decreasing the expression of NR3C2, SRC, and GAPDH.
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Affiliation(s)
- Wen Hou
- NHC Key Laboratory of Critical Care Medicine, Tianjin First Central Hospital, Tianjin, China
| | - Bao Wei
- Department of Surgery, Children's Hospital, Tianjin, China
| | - Hong Sheng Liu
- NHC Key Laboratory of Critical Care Medicine, Tianjin First Central Hospital, Tianjin, China
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14
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Dery KJ, Kupiec-Weglinski JW, Dong TS. The human microbiome in transplantation: the past, present, and future. Curr Opin Organ Transplant 2021; 26:595-602. [PMID: 34545840 DOI: 10.1097/mot.0000000000000922] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
PURPOSE OF REVIEW Over the past 20 years, DNA sequencing technology has transformed human microbiome research from identity characterizations to metagenomics approaches that reveal how microbials correlate with human health and disease. New studies are showing unprecedented opportunity for deep characterization of the human microbial ecosystem, with benefits to the field of organ transplantation. RECENT FINDINGS In the present review, we focus on past milestones of human-associated microbiota research, paying homage to microbiota pioneers. We highlight the role of sequencing efforts to provide insights beyond taxonomic identification. Recent advances in microbiome technology is now integrating high-throughput datasets, giving rise to multi'omics - a comprehensive assessment modeling dynamic biologic networks. Studies that show benefits and mechanisms in peritransplant antibiotic (Abx)-conditioned recipients are reviewed. We describe how next-generation microbial sequencing has the potential to combine with new technologies like phage therapy (PT) to translate into life-saving therapeutics. SUMMARY The study of the microbiome is advancing the field of transplantation by enhancing our knowledge of precision medicine. Sequencing technology has allowed the use of the microbiome as a biomarker to risk stratify patients. Further research is needed to better understand how microbiomes shape transplantation outcomes while informing immune cell - tissue crosstalk platforms.
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Affiliation(s)
- Kenneth J Dery
- The Dumont-UCLA Transplantation Center, Department of Surgery, Division of Liver and Pancreas Transplantation
| | - Jerzy W Kupiec-Weglinski
- The Dumont-UCLA Transplantation Center, Department of Surgery, Division of Liver and Pancreas Transplantation
| | - Tien S Dong
- Department of Medicine, Vatche & Tamar Manoukian Division of Digestive Diseases, David Geffen School of Medicine at UCLA, Los Angeles, California, USA
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15
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Zhang L, Li N, Cui LL, Xue FS, Zhu ZJ. Intraoperative Low-Dose Dexmedetomidine Administration Associated with Reduced Hepatic Ischemia-Reperfusion Injury in Pediatric Deceased Liver Transplantation: A Retrospective Cohort Study. Ann Transplant 2021; 26:e933354. [PMID: 34650026 PMCID: PMC8525313 DOI: 10.12659/aot.933354] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023] Open
Abstract
Background Dexmedetomidine (DEX) attenuates hepatic ischemia-reperfusion injury (HIRI) in adult liver transplantation (LT), but its effects on postoperative liver graft function in pediatric LT remain unclear. We sought to investigate whether intraoperative DEX administration was associated with improved liver graft function in pediatric LT recipients. It was hypothesized that DEX administration was associated with reduced HIRI and improved liver graft function. Material/Methods From November 2015 to May 2020, 54 deceased pediatric LT recipients were categorized into a control group and a DEX group. Intraoperatively, the DEX group received an additional infusion of DEX at 0.4 μg/kg/h from incision to the end of the operation in comparison with the control group. Preoperative, intraoperative, and postoperative data were reviewed. Postoperative liver enzyme levels and HIRI severity were assessed and compared. Independent risk factors for HIRI were determined by multivariate logistic regression analysis using a stepwise forward conditional method. Results We enrolled 28 and 26 patients in the DEX and control groups, respectively. Patients in the DEX group exhibited a reduced incidence of moderate-to-severe HIRI (88.5% vs 60.7%, P=0.020) and decreased level of serum alanine aminotransferase (median [interquartile range]: 407 [230–826] vs 714 [527–1492] IU/L, P=0.048) compared with the controls. Binary logistic analysis revealed that longer cold ischemia time (odds ratio [OR]=1.006; 95% confidence interval [CI]=1.000–1.013; P=0.044) and intraoperative DEX use (OR=0.198; 95% CI=0.045–0.878; P=0.033) were independent predictors for moderate-to-severe HIRI. Conclusions Intraoperative low-dose DEX administration was associated with a lower incidence of moderate-to-severe HIRI in pediatric deceased LT. However, further studies are needed to confirm our results and elucidate the underlying mechanisms.
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Affiliation(s)
- Liang Zhang
- Department of Anesthesiology, Beijing Friendship Hospital, Capital Medical University, Beijing, China (mainland)
| | - Na Li
- Department of Anesthesiology, Beijing Friendship Hospital, Capital Medical University, Beijing, China (mainland)
| | - Ling-Li Cui
- Department of Anesthesiology, Beijing Friendship Hospital, Capital Medical University, Beijing, China (mainland)
| | - Fu-Shan Xue
- Department of Anesthesiology, Beijing Friendship Hospital, Capital Medical University, Beijing, China (mainland)
| | - Zhi-Jun Zhu
- Division of Liver Transplantation, Department of General Surgery, Beijing Friendship Hospital, Capital Medical University, Beijing, China (mainland).,Clinical Center for Pediatric Liver Transplantation, Capital Medical University, Beijing, China (mainland).,Liver Transplantation Center, National Clinical Research Center for Digestive Diseases, Beijing, China (mainland)
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16
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Masior Ł, Grąt M. Methods of Attenuating Ischemia-Reperfusion Injury in Liver Transplantation for Hepatocellular Carcinoma. Int J Mol Sci 2021; 22:8229. [PMID: 34360995 PMCID: PMC8347959 DOI: 10.3390/ijms22158229] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2021] [Revised: 07/18/2021] [Accepted: 07/29/2021] [Indexed: 12/14/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the most frequent indications for liver transplantation. However, the transplantation is ultimately associated with the occurrence of ischemia-reperfusion injury (IRI). It affects not only the function of the graft but also significantly worsens the oncological results. Various methods have been used so far to manage IRI. These include the non-invasive approach (pharmacotherapy) and more advanced options encompassing various types of liver conditioning and machine perfusion. Strategies aimed at shortening ischemic times and better organ allocation pathways are still under development as well. This article presents the mechanisms responsible for IRI, its impact on treatment outcomes, and strategies to mitigate it. An extensive review of the relevant literature using MEDLINE (PubMed) and Scopus databases until September 2020 was conducted. Only full-text articles written in English were included. The following search terms were used: "ischemia reperfusion injury", "liver transplantation", "hepatocellular carcinoma", "preconditioning", "machine perfusion".
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Affiliation(s)
- Łukasz Masior
- Department of General, Vascular and Oncological Surgery, Medical University of Warsaw, Stępińska Street 19/25, 00-739 Warsaw, Poland
| | - Michał Grąt
- Department of General, Transplant and Liver Surgery, Medical University of Warsaw, Banacha Street 1A, 02-097 Warsaw, Poland;
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Tamai Y, Iwasa M, Eguchi A, Shigefuku R, Kamada Y, Miyoshi E, Takei Y. Rifaximin ameliorates intestinal inflammation in cirrhotic patients with hepatic encephalopathy. JGH Open 2021; 5:827-830. [PMID: 34263080 PMCID: PMC8264230 DOI: 10.1002/jgh3.12596] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2021] [Revised: 06/05/2021] [Accepted: 06/08/2021] [Indexed: 01/07/2023]
Abstract
Rifaximin (RFX) treatment can attenuate not only hyperammonemia but also Enterococcus faecalis translocation and 10-7G values, suggesting that RFX treatment may improve intestinal inflammation and result in better overall survival.
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Affiliation(s)
- Yasuyuki Tamai
- Department of Gastroenterology and HepatologyMie University Graduate School of MedicineTsuJapan
| | - Motoh Iwasa
- Department of Gastroenterology and HepatologyMie University Graduate School of MedicineTsuJapan
| | - Akiko Eguchi
- Department of Gastroenterology and HepatologyMie University Graduate School of MedicineTsuJapan
| | - Ryuta Shigefuku
- Department of Gastroenterology and HepatologyMie University Graduate School of MedicineTsuJapan
| | - Yoshihiro Kamada
- Department of Molecular Biochemistry and Clinical InvestigationOsaka University Graduate School of MedicineOsakaJapan
| | - Eiji Miyoshi
- Department of Molecular Biochemistry and Clinical InvestigationOsaka University Graduate School of MedicineOsakaJapan
| | - Yoshiyuki Takei
- Department of Gastroenterology and HepatologyMie University Graduate School of MedicineTsuJapan
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Trebicka J, Macnaughtan J, Schnabl B, Shawcross DL, Bajaj JS. The microbiota in cirrhosis and its role in hepatic decompensation. J Hepatol 2021; 75 Suppl 1:S67-S81. [PMID: 34039493 PMCID: PMC8973011 DOI: 10.1016/j.jhep.2020.11.013] [Citation(s) in RCA: 146] [Impact Index Per Article: 36.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/08/2020] [Revised: 11/09/2020] [Accepted: 11/10/2020] [Indexed: 02/06/2023]
Abstract
Cirrhosis - the common end-stage of chronic liver disease - is associated with a cascade of events, of which intestinal bacterial overgrowth and dysbiosis are central. Bacterial toxins entering the portal or systemic circulation can directly cause hepatocyte death, while dysbiosis also affects gut barrier function and increases bacterial translocation, leading to infections, systemic inflammation and vasodilation, which contribute to acute decompensation and organ failure. Acute decompensation and its severe forms, pre-acute-on-chronic liver failure (ACLF) and ACLF, are characterised by sudden organ dysfunction (and failure) and high short-term mortality. Patients with pre-ACLF and ACLF present with high-grade systemic inflammation, usually precipitated by proven bacterial infection and/or severe alcoholic hepatitis. However, no precipitant is identified in 30% of these patients, in whom bacterial translocation from the gut microbiota is assumed to be responsible for systemic inflammation and decompensation. Different microbiota profiles may influence the rate of decompensation and thereby outcome in these patients. Thus, targeting the microbiota is a promising strategy for the prevention and treatment of acute decompensation, pre-ACLF and ACLF. Approaches include the use of antibiotics such as rifaximin, faecal microbial transplantation and enterosorbents (e.g. Yaq-001), which bind microbial factors without exerting a direct effect on bacterial growth kinetics. This review focuses on the role of microbiota in decompensation and strategies targeting microbiota to prevent acute decompensation.
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Affiliation(s)
- Jonel Trebicka
- Translational Hepatology, Internal Medicine I, Goethe University Frankfurt, Germany; European Foundation for the Study of Chronic Liver Failure, Barcelona, Spain; Faculty of Health Sciences, University of Southern Denmark, Odense, Denmark.
| | - Jane Macnaughtan
- Institute for Liver and Digestive Health, Royal Free Campus, University College London, United Kingdom
| | - Bernd Schnabl
- Department of Medicine, University of California San Diego, La Jolla, CA, USA; Department of Medicine, VA San Diego Healthcare System, San Diego, CA, USA
| | - Debbie L Shawcross
- Institute of Liver Studies, Department of Inflammation Biology, School of Immunology and Microbial Sciences, Faculty of Life Sciences and Medicine, King's College London, Denmark Hill Campus, London, United Kingdom
| | - Jasmohan S Bajaj
- Virginia Commonwealth University and Central Virginia Veterans Healthcare System, Richmond, VA, USA
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19
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Recommendations and guidance on nutritional supplementation in the liver transplant setting. Transplantation 2021; 105:2528-2537. [PMID: 33724244 DOI: 10.1097/tp.0000000000003736] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
Malnutrition is a frequent complication in patients with cirrhosis and liver transplant (LT) candidates. It is highly related to sarcopenia, and their implications in morbidity and mortality go beyond the waiting list period throughout the post-LT. However, there are no specific interventions defined by guidelines, regarding the kind or the timing of the nutritional intervention to improve LT outcomes. Results from studies developed in the LT setting and evaluating their impact on the LT candidates or recipients are discussed in this review, and new research lines are presented.
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Dery KJ, Kadono K, Hirao H, Górski A, Kupiec-Weglinski JW. Microbiota in organ transplantation: An immunological and therapeutic conundrum? Cell Immunol 2020; 351:104080. [PMID: 32139071 DOI: 10.1016/j.cellimm.2020.104080] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2019] [Revised: 02/23/2020] [Accepted: 02/25/2020] [Indexed: 12/15/2022]
Abstract
The gastrointestinal (GI) tract microbiota is an environmental factor that regulates host immunity in allo-transplantation (allo-Tx). It is required for the development of resistance against pathogens and the stabilization of mucosa-associated lymphoid tissue. The gut-microbiota axis may also precipitate allograft rejection by producing metabolites that activate host cell-mediated and humoral immunity. Here, we discuss new insights into microbial immunomodulation, highlighting ongoing attempts to affect commensal colonization in an attempt to ameliorate allograft rejection cascade. Recent progress on the use of antibiotics to modulate GI microbiota diversity and innate-adaptive immune interface are discussed. Our focus on the microbiota's influence of endoplasmic reticulum (ER) stress and autophagy signaling through hepatic EP4/CHOP/LC3B platforms reveals a novel molecular pathway and potential biomarkers determining the progression of allo-Tx damage. Understanding and harnessing the potential of microbiome/bacteriophage therapies may offer safe and effective means for personalized treatment to reduce risks of infections and immunosuppression in allo-Tx.
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Affiliation(s)
- Kenneth J Dery
- Dumont-UCLA Transplantation Center, Department of Surgery, Division of Liver and Pancreas Transplantation, David Geffen School of Medicine at UCLA, Los Angeles 90095, CA, USA
| | - Kentaro Kadono
- Dumont-UCLA Transplantation Center, Department of Surgery, Division of Liver and Pancreas Transplantation, David Geffen School of Medicine at UCLA, Los Angeles 90095, CA, USA
| | - Hirofumi Hirao
- Dumont-UCLA Transplantation Center, Department of Surgery, Division of Liver and Pancreas Transplantation, David Geffen School of Medicine at UCLA, Los Angeles 90095, CA, USA
| | - Andrzej Górski
- Bacteriophage Laboratory and Phage Therapy Unit, Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Wroclaw, Poland
| | - Jerzy W Kupiec-Weglinski
- Dumont-UCLA Transplantation Center, Department of Surgery, Division of Liver and Pancreas Transplantation, David Geffen School of Medicine at UCLA, Los Angeles 90095, CA, USA.
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Cornide-Petronio ME, Álvarez-Mercado AI, Jiménez-Castro MB, Peralta C. Current Knowledge about the Effect of Nutritional Status, Supplemented Nutrition Diet, and Gut Microbiota on Hepatic Ischemia-Reperfusion and Regeneration in Liver Surgery. Nutrients 2020; 12:284. [PMID: 31973190 PMCID: PMC7071361 DOI: 10.3390/nu12020284] [Citation(s) in RCA: 36] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2019] [Revised: 01/13/2020] [Accepted: 01/15/2020] [Indexed: 02/06/2023] Open
Abstract
Ischemia-reperfusion (I/R) injury is an unresolved problem in liver resection and transplantation. The preexisting nutritional status related to the gut microbial profile might contribute to primary non-function after surgery. Clinical studies evaluating artificial nutrition in liver resection are limited. The optimal nutritional regimen to support regeneration has not yet been exactly defined. However, overnutrition and specific diet factors are crucial for the nonalcoholic or nonalcoholic steatohepatitis liver diseases. Gut-derived microbial products and the activation of innate immunity system and inflammatory response, leading to exacerbation of I/R injury or impaired regeneration after resection. This review summarizes the role of starvation, supplemented nutrition diet, nutritional status, and alterations in microbiota on hepatic I/R and regeneration. We discuss the most updated effects of nutritional interventions, their ability to alter microbiota, some of the controversies, and the suitability of these interventions as potential therapeutic strategies in hepatic resection and transplantation, overall highlighting the relevance of considering the extended criteria liver grafts in the translational liver surgery.
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Affiliation(s)
| | - Ana Isabel Álvarez-Mercado
- Department of Biochemistry and Molecular Biology II, School of Pharmacy, University of Granada, 18071 Granada, Spain;
- Institute of Nutrition and Food Technology “José Mataix,” Center of Biomedical Research, University of Granada, Avda. del Conocimiento s/n, 18016 Armilla, Granada, Spain
- Instituto de Investigación Biosanitaria ibs, GRANADA, Complejo Hospitalario Universitario de Granada, 18014 Granada, Spain
| | - Mónica B. Jiménez-Castro
- Institut d’Investigacions Biomèdiques August Pi I Sunyer (IDIBAPS), 08036 Barcelona, Spain; (M.E.C.-P.); (M.B.J.-C.)
| | - Carmen Peralta
- Institut d’Investigacions Biomèdiques August Pi I Sunyer (IDIBAPS), 08036 Barcelona, Spain; (M.E.C.-P.); (M.B.J.-C.)
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), 08036 Barcelona, Spain
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