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Mapping the metabolic responses to oxaliplatin-based chemotherapy with in vivo spatiotemporal metabolomics

Journal of Pharmaceutical Analysis 2024年第2期14卷 196-210页

作者： Mariola Olkowicz Khaled Ramadan Hernando Rosales-Solano Miao Yu Aizhou Wang Marcelo Cypel Janusz Pawliszyn Department of Chemistry University of WaterlooWaterlooONCanada Jagiellonian Centre for Experimental Therapeutics(JCET) Jagiellonian UniversityKrakowPoland Latner Thoracic Surgery Research Laboratories Toronto General Hospital Research InstituteUniversity Health NetworkTorontoONCanada The Jackson Laboratory JAX Genomic MedicineFarmingtonCTUSA Division of Thoracic Surgery Department of SurgeryUniversity Health NetworkUniversity of TorontoToronto Lung Transplant ProgramTorontoONCanada

Adjuvant chemotherapy improves the survival outlook for patients undergoing operations for lung metastases caused by colorectal cancer (CRC). However, a multidisciplinary approach that evaluates several factors related to patient and tumor characteristics is necessary for managing chemotherapy treatment in metastatic CRC patients with lung disease, as such factors dictate the timing and drug regimen, which may affect treatment response and prognosis. In this study, we explore the potential of spatial metabolomics for evaluating metabolic phenotypes and therapy outcomes during the local delivery of the anticancer drug, oxaliplatin, to the lung. 12 male Yorkshire pigs underwent a 3 h left lung in vivo lung perfusion (IVLP) with various doses of oxaliplatin (7.5, 10, 20, 40, and 80 mg/L), which were administered to the perfusion circuit reservoir as a bolus. Biocompatible solid-phase microextraction (SPME) microprobes were combined with global metabolite profiling to obtain spatiotemporal information about the activity of the drug, determine toxic doses that exceed therapeutic efficacy, and conduct a mechanistic exploration of associated lung injury. Mild and subclinical lung injury was observed at 40 mg/L of oxaliplatin, and significant compromise of the hemodynamic lung function was found at 80 mg/L. This result was associated with massive alterations in metabolic patterns of lung tissue and perfusate, resulting in a total of 139 discriminant compounds. Uncontrolled inflammatory response, abnormalities in energy metabolism, and mitochondrial dysfunction next to accelerated kynurenine and aldosterone production were recognized as distinct features of dysregulated metabolipidome. Spatial pharmacometabolomics may be a promising tool for identifying pathological responses to chemotherapy.

关键词： Pulmonary metastases Colorectal cancer Adjuvant chemotherapy In vivo lung chemo-perfusion Solid-phase microextraction(SPME)microprobes Spatial metabolomics

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Disorders of potassium homeostasis after kidney transplantation

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World Journal of transplantation 2024年第3期14卷 40-51页

作者： Abdelhamid Aboghanem G V Ramesh Prasad School of Medicine University of TorontoToronto M5C 2T2OntarioCanada Kidney transplant program St.Michael's HospitalToronto M5C 2T2OntarioCanada

Disturbances of potassium balance are often encountered when managing kidney transplant recipients(KTR).Both hyperkalemia and hypokalemia may present either as medical emergencies or chronic outpatient *** the high incidence of hyperkalemia and its potential life-threatening implications,consensus on its management in KTR is *** in KTR is also well-described,although it is given less attention by clinicians compared to *** article discusses the etiology,pathophysiology and management of both types of potassium disorders in *** any emergent situation has been corrected,treatment approaches include correcting insulin deficiency if present,adjusting non-immunosuppressive and immunosuppressive medications,elimi-nating or supplementing potassium as needed,and dietary *** commonly of multifactorial etiology,ascertaining the specific cause in a particular patient will help guide successful *** KTR through regular laboratory testing is essential to detect serious disturbances in potassium balance since patients are often asymptomatic.

关键词： Balance Dialysis Hyperkalemia Hypokalemia Kidney Metabolism Potassium

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Three-dimensional cell-based strategies for liver regeneration

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BIOCELL 2024年第7期48卷 1023-1036页

作者： DAN GUO XI XIA JIAN YANG Liver transplant Center Transplant CenterWest China HospitalSichuan UniversityChengdu610041China Frontiers Medical Center Tianfu Jincheng LaboratoryChengdu610212China

Liver regeneration and the development of effective therapies for liver failure remain formidable challenges in modern *** recent years,the utilization of 3D cell-based strategies has emerged as a promising approach for addressing these urgent clinical *** review provides a thorough analysis of the application of 3D cell-based approaches to liver regeneration and their potential impact on patients with end-stage liver ***,we discuss various 3D culture models that incorporate hepatocytes and stem cells to restore liver function and ameliorate the consequences of liver ***,we explored the challenges in transitioning these innovative strategies from preclinical studies to clinical *** collective insights presented herein highlight the signiﬁcance of 3D cell-based strategies as a transformative paradigm for liver regeneration and improved patient care.

关键词： Three-Dimensional Liver regeneration Organoids Stem cells Cell therapy

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Mitochondrial dysfunction affects hepatic immune and metabolic remodeling in patients with hepatitis B virus-related acute-onchronic liver failure

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World Journal of Gastroenterology 2024年第8期30卷 881-900页

作者： Yu Zhang Xiao-Ling Tian Jie-Qun Li Dong-Sheng Wu Qiang Li Bin Chen Department of Hepatology Institute of HepatologyThe First Affiliated Hospital of Hunan University of Chinese MedicineChangsha 410021Hunan ProvinceChina Department of Liver transplant Transplant Medical Research CenterThe Second Xiangya Hospital of Central South UniversityChangsha 410011Hunan ProvinceChina Department of Surgery The First Affiliated Hospital of Hunan University of Chinese MedicineChangsha 410021Hunan ProvinceChina

BACKGROUND Immune dysregulation and metabolic derangement have been recognized as key factors that contribute to the progression of hepatitis B virus(HBV)-related acute-on-chronic liver failure(ACLF).However,the mechanisms underlying immune and metabolic derangement in patients with advanced HBV-ACLF are *** To identify the bioenergetic alterations in the liver of patients with HBV-ACLF causing hepatic immune dysregulation and metabolic *** Liver samples were collected from 16 healthy donors(HDs)and 17 advanced HBV-ACLF patients who were eligible for liver *** mitochondrial ultrastructure,metabolic characteristics,and immune microenvironment of the liver were *** focus was given to organic acid metabolism as well as the function and subpopulations of macrophages in patients with *** Compared with HDs,there was extensive hepatocyte necrosis,immune cell infiltration,and ductular reaction in patients with *** patients,the liver suffered severe hypoxia,as evidenced by increased expression of hypoxia-inducible factor-1α.Swollen mitochondria and cristae were observed in the liver of *** number,length,width,and area of mitochondria were adaptively increased in *** metabolomics analysis revealed that mitochondrial oxidative phosphorylation decreased,while anaerobic glycolysis was enhanced in patients with *** findings suggested that,to a greater extent,hepa-tocytes used the extra-mitochondrial glycolytic pathway as an energy *** with HBV-ACLF had elevated levels of chemokine C-C motif ligand 2 in the liver homogenate,which stimulates peripheral monocyte infiltration into the *** and functional analysis of macrophage subsets revealed that patients with ACLF had a high abundance of CD68^(+)HLA-DR^(+)macrophages and elevated levels of both interleukin-1βand transforming growth factor-β1 in their *** abundance of CD206^(+)CD163^(+)macrophag

关键词： Acute-on-chronic liver failure Hypoxia-inducible factor-1α Mitochondria Metabolic phenotype Immune cells

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Protective effects of cyclosporine and its analog NIM-811 in a murine model of hepatic ischemia-reperfusion injury

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Liver Research 2024年第1期8卷 46-53页

作者： Joshua Hefler Rena Pawlick Braulio A.Marfil-Garza Aducio Thiesen Nerea Cuesta-Gomez Sanaz Hatami Darren H.Freed Constantine Karvellas David L.Bigam A.M.James Shapiro Department of Surgery Faculty of Medicine&DentistryUniversity of AlbertaEdmontonABCanada Department of Medicine Faculty of Medicine&DentistryUniversity of AlbertaEdmontonABCanada CHRISTUS-LatAm Hub Excellence&Innovation Center MonterreyMexico Alberta Diabetes Institute University of AlbertaEdmontonABCanada Clinical Islet transplant program University of AlbertaEdmontonABCanada Department of Laboratory Medicine&Pathology Faculty of Medicine&DentistryUniversity of AlbertaEdmontonABCanada

Background and aim:The liver is susceptible to ischemia-reperfusion injury(IRI)during hepatic surgery,when the vessels are compressed to control bleeding,or liver transplantation,when there is an obligate period of *** hallmark of IRI comprises mitochondrial dysfunction,which generates reactive oxygen species,and cell death through necrosis or ***(CsA),which is a well-known immunosuppressive agent that inhibits calcineurin,has the additional effect of inhibiting the mito-chondrial permeability transition pore(mPTP),thereby,preventing mitochondrial swelling and ***-811,which is the nonimmunosuppressive analog of CsA,has a similar effect on the *** this study,we tested the effect of both agents on mitigating warm hepatic IRI in a murine *** and methods:Before ischemic insult,the mice were administered with intraperitoneal normal saline(control);CsA at 2.5,10,or 25 mg/kg;or NIM-811 at 10 mg/***,the mice were subjected to partial warm hepatic ischemia by selective pedicle clamping for 60 min,followed by 6 h of recovery after *** alanine transaminase(ALT)was measured,and the liver tissue was examined histologically for the presence of apoptosis and the levels of inflammatory ***:Compared with the control mice,the mice treated with 10 and 25 mg/kg of CsA and NIM-811 had significantly lower ALT levels(P<0.001,0.007,and 0.031,respectively).Moreover,the liver tissue showed reduced histological injury scores after treatment with CsA at 2.5,10,and 25 mg/kg and NIM-811(P=0.041,<0.001,0.003,and 0.043,respectively)and significant decrease in apoptosis after treatment with CsA at all doses(P=0.012,0.007,and<0.001,respectively).Levels of the pro-inflammatory cyto-kines,particularly interleukin(IL)-1β,IL-2,IL-4,IL-10,and keratinocyte chemoattractant/human growth-regulated oncogene significantly decreased in the mice treated with the highest dose of CsA(25 mg/kg)than those in the control ***

关键词： Cyclosporine(CsA) Cyclosporine analogue Liver surgery Ischemia-reperfusion injury(IRI) Animal model NIM-811

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Outcomes in pediatric recipients of single kidney transplantation from pediatric donors with acute kidney injury:A single-center pilot study

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Chinese Medical Journal 2024年第12期137卷 1489-1491页

作者： Qiang Zhang Yanxu Chen Haiyue Yu Jun Li Chenglin Wu Sizhe Long Pengan Li Qian Fu Huanxi Zhang Xiaojun Su Bowen Xu Longshan Liu Changxi Wang Organ transplant Center The First Affiliated HospitalSun Yat-sen UniversityGuangzhouGuangdong 510080China Stomatological Hospital Southern Medical UniversityGuangzhouGuangdong 510280China Center for Information Technology and Statistics The First Affiliated HospitalSun Yat-sen UniversityGuangzhouGuangdong 510080China Guangdong Provincial Key Laboratory of Organ Donation and transplant Immunology GuangzhouGuangdong 510080China Guangdong Provincial Key Laboratory Guangdong Provincial International Cooperation Base of Science and Technology(Organ transplantation) GuangzhouGuangdong 510080China

To the Editor:The shortage of deceased donor(DD)kidneys for transplantation remains a persistent *** the potential reversibility of acute kidney injury(AKI)lesions,kidneys from pediatric donors with AKI are often underutilized,especially in the context of pediatric *** implementing single kidney transplantation(SKT)from pediatric donors to pediatric recipients(PTP),we can optimize the utilization of available kidneys and increase the number of pediatric recipients.

关键词： pediatric kidney acute

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Validation and performance of three scoring systems for predicting primary non-function and early allograft failure after liver transplantation

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Hepatobiliary & Pancreatic Diseases International 2024年第5期23卷 463-471页

作者： Yu Nie Jin-Bo Huang Shu-Jiao He Hua-Di Chen Jun-Jun Jia Jing-Jing Li Xiao-Shun He Qiang Zhao General Surgery Center Department of Hepatobiliary Surgery IIResearch Center for Artificial Organ and Tissue EngineeringGuangzhou Clinical Research and Transformation Center for Artificial LiverInstitute of Regenerative MedicineZhujiang HospitalSouthern Medical UniversityGuangzhou 510515China Organ transplant Center the First Affiliated HospitalSun Yat-sen UniversityGuangzhou 510080China Guangdong Provincial Key Laboratory of Organ Donation and transplant Immunology Guangzhou 510080China Guangdong Provincial International Cooperation Base of Science and Technology Guangzhou 510080China Division of Hepatobiliary Pancreatic Surgery the First Affiliated HospitalZhejiang University School of MedicineHangzhou 310003China

Background: Primary non-function(PNF) and early allograft failure(EAF) after liver transplantation(LT) seriously affect patient outcomes. In clinical practice, effective prognostic tools for early identifying recipients at high risk of PNF and EAF were urgently needed. Recently, the Model for Early Allograft Function(MEAF), PNF score by King's College(King-PNF) and Balance-and-Risk-Lactate(BAR-Lac) score were developed to assess the risks of PNF and EAF. This study aimed to externally validate and compare the prognostic performance of these three scores for predicting PNF and EAF. Methods: A retrospective study included 720 patients with primary LT between January 2015 and December 2020. MEAF, King-PNF and BAR-Lac scores were compared using receiver operating characteristic(ROC) and the net reclassification improvement(NRI) and integrated discrimination improvement(IDI) analyses. Results: Of all 720 patients, 28(3.9%) developed PNF and 67(9.3%) developed EAF in 3 months. The overall early allograft dysfunction(EAD) rate was 39.0%. The 3-month patient mortality was 8.6% while 1-year graft-failure-free survival was 89.2%. The median MEAF, King-PNF and BAR-Lac scores were 5.0(3.5–6.3),-2.1(-2.6 to-1.2), and 5.0(2.0–11.0), respectively. For predicting PNF, MEAF and King-PNF scores had excellent area under curves(AUCs) of 0.872 and 0.891, superior to BAR-Lac(AUC = 0.830). The NRI and IDI analyses confirmed that King-PNF score had the best performance in predicting PNF while MEAF served as a better predictor of EAD. The EAF risk curve and 1-year graft-failure-free survival curve showed that King-PNF was superior to MEAF and BAR-Lac scores for stratifying the risk of EAF. Conclusions: MEAF, King-PNF and BAR-Lac were validated as practical and effective risk assessment tools of PNF. King-PNF score outperformed MEAF and BAR-Lac in predicting PNF and EAF within 6 months. BAR-Lac score had a huge advantage in the prediction for PNF without post-transplant variables. Proper use

关键词： Primary non-function Early allograft failure Risk predicting model Liver transplantation

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Predicting major adverse cardiovascular events after orthotopic liver transplantation using a supervised machine learning model:A cohort study

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World Journal of Hepatology 2024年第2期16卷 193-210页

作者： Jonathan Soldera Leandro Luis Corso Matheus Machado Rech Vinícius Remus Ballotin Lucas Goldmann Bigarella Fernanda Tomé Nathalia Moraes Rafael Sartori Balbinot Santiago Rodriguez Ajacio Bandeira de Mello Brandão Bruno Hochhegger Post Graduate program at Acute Medicine and Gastroenterology University of South WalesCardiff CF371DLUnited Kingdom Postgraduate program in Pathology Federal University of Health Sciences of Porto Alegre(UFCSPA)Porto Alegre 90050-170Brazil Department of Engineering Universidade de Caxias do SulCaxias do Sul 95070-560Brazil School of Medicine Universidade de Caxias do SulCaxias do Sul 95070-560Brazil Postgraduate program in Hepatology Federal University of Health Sciences of Porto Alegre(UFCSPA)Porto Alegre 90050-170Brazil

BACKGROUND Liver transplant(LT)patients have become older and *** rate of post-LT major adverse cardiovascular events(MACE)has increased,and this in turn raises 30-d post-LT *** cardiac stress testing loses accuracy when applied to pre-LT cirrhotic *** To assess the feasibility and accuracy of a machine learning model used to predict post-LT MACE in a regional *** This retrospective cohort study involved 575 LT patients from a Southern Brazilian academic *** developed a predictive model for post-LT MACE(defined as a composite outcome of stroke,new-onset heart failure,severe arrhythmia,and myocardial infarction)using the extreme gradient boosting(XGBoost)machine learning *** addressed missing data(below 20%)for relevant variables using the k-nearest neighbor imputation method,calculating the mean from the ten nearest neighbors for each *** modeling dataset included 83 features,encompassing patient and laboratory data,cirrhosis complications,and pre-LT cardiac *** performance was assessed using the area under the receiver operating characteristic curve(AUROC).We also employed Shapley additive explanations(SHAP)to interpret feature *** dataset was split into training(75%)and testing(25%)*** was evaluated using the Brier *** followed Transparent Reporting of a Multivariable Prediction Model for Individual Prognosis or Diagnosis guidelines for ***-learn and SHAP in Python 3 were used for all *** supplementary material includes code for model development and a user-friendly online MACE prediction *** Of the 537 included patients,23(4.46%)developed in-hospital MACE,with a mean age at transplantation of 52.9 *** majority,66.1%,were *** XGBoost model achieved an impressive AUROC of 0.89 during the training *** model exhibited accuracy,precision,recall,and F1-score values of 0.84,0.85,0.80,and 0.79,***

关键词： Liver transplantation Major adverse cardiac events Machine learning Myocardial perfusion imaging Stress test

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加拿大多伦多肺移植新进展(附视频)

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中华移植杂志（电子版） 2011年第2期5卷 48-49页

作者： Thomas K. Waddell toronto lung transplant program Division of ThoracicSurgeryToronto General Hospital

（编者按：本文根据Waddell教授在2010年第5届全国心肺移植高级研讨会上讲课内容归纳整理）自1983年多伦多总院肺移植团队完成世界上第1例成功的肺移植以来,该院肺移植中心每年（1983年至2008年5月）的手术例数稳步增长,受者术后病死率... 详细信息

（编者按：本文根据Waddell教授在2010年第5届全国心肺移植高级研讨会上讲课内容归纳整理）自1983年多伦多总院肺移植团队完成世界上第1例成功的肺移植以来,该院肺移植中心每年（1983年至2008年5月）的手术例数稳步增长,受者术后病死率明显下降。肺移植手术适应证的前三项疾病分别为慢性阻塞性肺疾病（33%）、

关键词：肺移植多伦多禁忌证体外膜肺氧合离体肺灌注供者视频

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FGF21-mediated autophagy:Remodeling the homeostasis in response to stress in liver diseases

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Genes & Diseases 2024年第3期11卷 264-274页

作者： Wei Shen Modan Yang Hao Chen Chiy He Huigang Li Xinyu Yang Jianyong Zhuo Zuyuan Lin Zhihang Hu Di Lu Xiao Xu Zhejiang University School of Medicine HangzhouZhejiang 310058China Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province Department of Hepatobiliary and Pancreatic SurgeryAffiliated Hangzhou First People's HospitalZhejiang University School of MedicineHangzhouZhejiang 310006China The Institute for Organ Repair and Regenerative Medicine of Hangzhou HangzhouZhejiang 310006China Institute of Organ transplantation Zhejiang UniversityHangzhouZhejiang 310003China National Center for Healthcare Quality Management in Liver transplant HangzhouZhejiang 310003China

Liver diseases are worldwide problems closely associated with various stresses,such as endoplasmic reticulum *** exact interplay between stress and liver diseases remains *** plays an essential role in maintaining homeostasis,and recent studies indicate tight crosstalk between stress and autophagy in liver *** the bal-ance between damage and autophagy is broken,autophagy can no longer resist injury or main-tain *** recent years,FGF21(fibroblast growth factor 21)-induced autophagy has attracted much ***21 is regarded as a stress hormone and can be up-regulated by an abundance of signaling pathways in response to ***,increased FGF21 activates autophagy by a complicated signaling network in which mTOR plays a pivotal *** review summarizes the mechanism of FGF21-mediated autophagy and its derived application in the defense of stress in liver diseases and offers a glimpse into its promising prospect in future clinical practice.

关键词： Autophagy Fibroblast growth factor 21 Liver diseases mTOR Stress

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