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Siriwong N, Sriphoosanaphan S, Decharatanachart P, Yongpisarn T, Kerr SJ, Treeprasertsuk S, Tiyarattanachai T, Apiparakoon T, Hagström H, Akbari C, Ekstedt M, Yip TCF, Wong GLH, Ito T, Ishigami M, Toyoda H, Peleg N, Shlomai A, Seko Y, Sumida Y, Kawanaka M, Hino K, Chaiteerakij R. Role of noninvasive tests on the prediction of hepatocellular carcinoma in nonalcoholic fatty liver disease patients without cirrhosis: a systematic review and meta-analysis of aggregate and individual patient data. Eur J Gastroenterol Hepatol 2025; 37:358-369. [PMID: 39919008 DOI: 10.1097/meg.0000000000002912] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/09/2025]
Abstract
BACKGROUND Nonalcoholic fatty liver disease (NAFLD) has been identified as an emerging risk factor for hepatocellular carcinoma (HCC). Identifying non-cirrhotic NAFLD patients at risk for HCC is crucial. We aimed to investigate the utility of noninvasive tests (NITs) as predictors for HCC and to determine optimal and cost-effective NIT cutoffs for HCC surveillance in non-cirrhotic NAFLD patients. METHODS Medline, EMBASE, and Scopus databases were searched for studies evaluating the relationship between NITs and HCC in this population. Random-effects models were used to estimate hazard ratios or risk ratios and 95% confidence interval (95% CI). Cutoffs of NITs for identifying high-risk patients for HCC were determined. RESULTS This systematic review comprised 20 studies. A meta-analysis of 379 194 patients was conducted using six studies with individual patient data and five studies with aggregate data. Among NITs studied, fibrosis-4 index (FIB-4), aspartate aminotransferase to platelet ratio index (APRI), and NAFLD fibrosis score (NFS) were significantly associated with HCC, with pooled risk ratio (95% CI) of 9.21 (5.79-14.64), pooled hazard ratio of 12.53 (6.57-23.90), and 13.32 (6.48-27.37), respectively. FIB-4, APRI, and NFS of more than 2.06, 0.65, and 0.51 resulted in the highest area under the receiver operating characteristics of 0.83, 0.80, and 0.85, respectively. Surveillance in patients with FIB-4 ≥ 5.91 and NFS ≥ 2.85 would be cost-effective with an annual HCC incidence of ≥15 per 1000 patient-years. CONCLUSION FIB-4, APRI, and NFS are associated with HCC development in non-cirrhotic NAFLD patients. Different NIT cutoffs may be used to enroll high-risk NAFLD patients for HCC surveillance, according to resource availability in different settings.
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Affiliation(s)
- Nanicha Siriwong
- Division of Gastroenterology, Department of Medicine, Faculty of Medicine, Chulalongkorn University, and King Chulalongkorn Memorial Hospital, Thai Red Cross Society
| | - Supachaya Sriphoosanaphan
- Division of Gastroenterology, Department of Medicine, Faculty of Medicine, Chulalongkorn University, and King Chulalongkorn Memorial Hospital, Thai Red Cross Society
| | | | - Tanat Yongpisarn
- Division of Gastroenterology, Department of Medicine, Faculty of Medicine, Chulalongkorn University, and King Chulalongkorn Memorial Hospital, Thai Red Cross Society
| | - Stephen J Kerr
- Biostatistics Excellence Centre, Faculty of Medicine, Chulalongkorn University
| | - Sombat Treeprasertsuk
- Division of Gastroenterology, Department of Medicine, Faculty of Medicine, Chulalongkorn University, and King Chulalongkorn Memorial Hospital, Thai Red Cross Society
| | - Thodsawit Tiyarattanachai
- Department of Medicine, Faculty of Medicine, Chulalongkorn University, and King Chulalongkorn Memorial Hospital, Thai Red Cross Society, Bangkok, Thailand
| | - Terapap Apiparakoon
- Division of Gastroenterology, Department of Medicine, Faculty of Medicine, Chulalongkorn University, and King Chulalongkorn Memorial Hospital, Thai Red Cross Society
| | - Hannes Hagström
- Department of Medicine, Huddinge, Karolinska Institutet
- Division of Hepatology, Department of Upper GI, Karolinska University Hospital, Stockholm
| | | | - Mattias Ekstedt
- Division of Diagnostics and Specialist Medicine, Department of Health, Medicine and Caring Sciences, Linköping University, Linköping, Sweden
| | - Terry Cheuk-Fung Yip
- Department of Medicine and Therapeutics
- Medical Data Analytics Centre
- State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong, Hong Kong
| | - Grace Lai-Hung Wong
- Department of Medicine and Therapeutics
- Medical Data Analytics Centre
- State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong, Hong Kong
| | - Takanori Ito
- Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, Nagoya
| | - Masatoshi Ishigami
- Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, Nagoya
| | - Hidenori Toyoda
- Department of Gastroenterology and Hepatology, Ogaki Municipal Hospital, Gifu, Japan
| | - Noam Peleg
- Department of Gastroenterology and Hepatology, Rabin Medical Center, Beilinson Hospital, Petach-Tikva
| | - Amir Shlomai
- Department of Medicine D, Beilinson Hospital, Rabin Medical Center and the Faculty of Medical and Health Sciences, Tel Aviv University, Tel Aviv, Israel
| | - Yuya Seko
- Department of Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, Kyoto
| | - Yoshio Sumida
- Division of Hepatology and Pancreatology, Department of Internal Medicine, Aichi Medical University, Nagakute, Aichi
| | - Miwa Kawanaka
- Department of General Internal Medicine, Kawasaki Medical Center, Kawasaki Medical School, Okayama
| | - Keisuke Hino
- Department of Hepatology and Pancreatology, Kawasaki Medical School, Kurashiki, Japan
| | - Roongruedee Chaiteerakij
- Division of Gastroenterology, Department of Medicine, Faculty of Medicine, Chulalongkorn University, and King Chulalongkorn Memorial Hospital, Thai Red Cross Society
- Center of Excellence for Innovation and Endoscopy in Gastrointestinal Oncology, Division of Gastroenterology, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
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Yasuda K, Nishijima A, Inoue T, Takagi T, Tanabe K, Minakuchi J, Arai S, Miyazaki T. Release of apoptosis inhibitor of macrophage (AIM) from pentameric IgM in serum predicts prognosis after hemodialysis initiation. COMMUNICATIONS MEDICINE 2025; 5:15. [PMID: 39794503 PMCID: PMC11724077 DOI: 10.1038/s43856-025-00735-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2024] [Accepted: 01/06/2025] [Indexed: 01/13/2025] Open
Abstract
BACKGROUND The optimal timing for initiating dialysis and prognostic markers in chronic kidney disease (CKD) patients are under debate, with mortality and cardiovascular risks varying among patients. This study investigates whether the apoptosis inhibitor of macrophage (AIM), which is mostly bound to pentameric IgM, could serve as an effective indicator. METHODS We prospectively followed 423 patients at dialysis initiation and 563 at various CKD stages. AIM dissociation from IgM and other serum components were measured in their serum samples. In vitro treatment of IgM-AIM complexes with their serum was conducted to assess AIM release from IgM. Survival analysis determined the associations of each variable with mortality and cardiovascular risk, and a cutoff value was calculated and validated using cross-validation. RESULTS AIM dissociation from IgM increases with CKD progression and correlates with the serum uremic state, as shown by enhanced AIM release from IgM in vitro with sera from patients starting dialysis, but not those at earlier CKD stages. Patients at dialysis initiation with high proportion of serum IgM-free AIM (fAIM%) show elevated uremic toxins and other toxic metabolites, higher mortality, and increased cardiovascular risk compared to those with low fAIM%. This prognostic association is not seen with other CKD biomarkers, such as eGFR, creatinine, or inositol-phosphate. We determined the fAIM% cutoff of 46.27%, which predicts mortality two years post-dialysis initiation. CONCLUSIONS These findings suggest that the serum fAIM% could function as a prognostic marker at dialysis initiation and may have potential as a criterion for determining dialysis timing.
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Affiliation(s)
- Keisuke Yasuda
- The Institute for AIM Medicine (IAM), Tokyo, Japan
- Laboratory of Molecular Biomedicine for Pathogenesis, Center for Disease Biology and Integrative Medicine, Faculty of Medicine, The University of Tokyo, Tokyo, Japan
| | | | | | - Toshio Takagi
- Department of Urology, Tokyo Women's Medical University, Tokyo, Japan
| | - Kazunari Tanabe
- Department of Urology, Shonan Kamakura General Hospital, Kamakura, Japan
| | | | - Satoko Arai
- The Institute for AIM Medicine (IAM), Tokyo, Japan.
| | - Toru Miyazaki
- The Institute for AIM Medicine (IAM), Tokyo, Japan.
- LEAP, Japan Agency for Medical Research and Development, Tokyo, Japan.
- Laboratoire d'ImmunoRhumatologie Moléculaire, Plateforme GENOMAX, Institut National de la Santé et de la Recherche Médicale UMR_S 1109, Faculté de Médecine, Fédération Hospitalo-Universitaire OMICARE, Fédération de Médecine, Translationnelle de Strasbourg, Laboratory of Excellence TRANSPLANTEX, Université de Strasbourg, Strasbourg, France.
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Zhao J, Hu Z, Zheng X, Lin Y, Liu X, Zhang J, Peng J, Gao H. Blood biomarkers of hepatocellular carcinoma: a critical review. Front Cell Dev Biol 2024; 12:1489836. [PMID: 39650722 PMCID: PMC11621223 DOI: 10.3389/fcell.2024.1489836] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2024] [Accepted: 11/13/2024] [Indexed: 12/11/2024] Open
Abstract
Hepatocellular Carcinoma (HCC) is a malignant tumor with high morbidity and mortality worldwide, which represents a serious threat to human life, health and quality of life. Blood-based detection is essential for HCC screening, early diagnosis, prognosis evaluation, and surveillance. Current non-invasive detection strategy including serum alpha-fetoprotein (AFP), ultrasound, computerized tomography, and magnetic resonance imaging. The limited specificity of an AFP and the dependence on operator experience and diagnostic personnel for ultrasound have constrained their utility in early HCC diagnosis. In recent years, with the development of various detection technologies, there has been an increasing focus on exploring blood-based detection markers for HCC. The types of markers include protein markers, DNA mutation, DNA epigenetic modification, mRNA, miRNA, and so on. However, numerous methodological and biological factors limit the clinical sensitivity and generalization performance of these new biomarkers. In this review, we describe the state-of-the-art technologies for cfDNA analysis, and discuss outstanding biological and technical challenges that, if addressed, would substantially improve HCC diagnostics and patient care.
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Affiliation(s)
- Junsheng Zhao
- Key Laboratory of Artificial Organs and Computational Medicine in Zhejiang Province, Shulan International Medical College, Zhejiang Shuren University, Hangzhou, China
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Zekai Hu
- Key Laboratory of Artificial Organs and Computational Medicine in Zhejiang Province, Shulan International Medical College, Zhejiang Shuren University, Hangzhou, China
| | - Xiaoping Zheng
- Hangzhou Tongchuang Medical Laboratory, Department of pathology, Hangzhou, China
| | - Yajie Lin
- Key Laboratory of Artificial Organs and Computational Medicine in Zhejiang Province, Shulan International Medical College, Zhejiang Shuren University, Hangzhou, China
| | - Xiao Liu
- Key Laboratory of Artificial Organs and Computational Medicine in Zhejiang Province, Shulan International Medical College, Zhejiang Shuren University, Hangzhou, China
| | - Junjie Zhang
- Key Laboratory of Artificial Organs and Computational Medicine in Zhejiang Province, Shulan (Hangzhou) Hospital Affiliated to Shulan International Medical College, Zhejiang Shuren University, Hangzhou, China
| | - Jing Peng
- Department of Breast Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Hainv Gao
- Key Laboratory of Artificial Organs and Computational Medicine in Zhejiang Province, Shulan International Medical College, Zhejiang Shuren University, Hangzhou, China
- Key Laboratory of Artificial Organs and Computational Medicine in Zhejiang Province, Shulan (Hangzhou) Hospital Affiliated to Shulan International Medical College, Zhejiang Shuren University, Hangzhou, China
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Xu P, Liu M, Liu M, Shen A. Management of non-alcoholic fatty liver disease-associated hepatocellular carcinoma. Biosci Trends 2024; 18:431-443. [PMID: 39428499 DOI: 10.5582/bst.2024.01295] [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] [Indexed: 10/22/2024]
Abstract
In recent years, with the decline in HBV and HCV infections, there has been a corresponding reduction in both the morbidity and mortality of virus-associated HCC. Nevertheless, rising living standards, coupled with the increasing prevalence of metabolic disorders like diabetes and obesity, have led to a rapid surge in non-alcoholic fatty liver disease-associated hepatocellular carcinoma (NAFLD-HCC) incidence. The mechanisms underlying the progression from NAFLD to NAFLD-HCC are multifaceted and remain incompletely understood. Current research suggests that genetic predisposition, metabolic dysregulation, lipotoxicity, oxidative stress, and inflammation are key contributing factors. Given the complexity of these mechanisms and the frequent occurrence of metabolic comorbidities like type 2 diabetes mellitus (T2DM) and cardiovascular disease in NAFLD-HCC patients, there is a pressing need for tailored therapeutic strategies, along with novel prevention, monitoring, and treatment approaches that are personalized to the patient's pathophysiology. Due to the limited depth of research, incomplete understanding of pathogenesis, and insufficient clinical data on NAFLD-HCC treatment, current therapeutic approaches largely rely on tumor staging. In this review, we synthesize current research on the pathogenesis, surveillance, diagnosis, treatment, and prevention of NAFLD-HCC, and offer perspectives for future studies, particularly regarding its underlying mechanisms.
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Affiliation(s)
- Peijun Xu
- Department of Hepatobiliary Pancreatic Cancer Center, Cancer Hospital, School of Medicine, Chongqing University, Chongqing, China
| | - Maoyun Liu
- Department of Hepatobiliary Pancreatic Cancer Center, Cancer Hospital, School of Medicine, Chongqing University, Chongqing, China
| | - Miao Liu
- Department of Gastrointestinal Cancer Center, Cancer Hospital, School of Medicine, Chongqing University, Chongqing, China
| | - Ai Shen
- Department of Hepatobiliary Pancreatic Cancer Center, Cancer Hospital, School of Medicine, Chongqing University, Chongqing, China
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Cao Y, Hu B, Fan Y, Wang W, Chi M, Nasser MI, Ma K, Liu C. The effects of apoptosis inhibitor of macrophage in kidney diseases. Eur J Med Res 2024; 29:21. [PMID: 38178221 PMCID: PMC10765713 DOI: 10.1186/s40001-023-01597-3] [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: 08/27/2023] [Accepted: 12/14/2023] [Indexed: 01/06/2024] Open
Abstract
Kidney disease is a progressive and irreversible condition in which immunity is a contributing factor that endangers human health. It is widely acknowledged that macrophages play a significant role in developing and causing numerous kidney diseases. The increasing focus on the mechanism by which macrophages express apoptosis inhibitor of macrophages (AIM) in renal diseases has been observed. AIM is an apoptosis inhibitor that stops different things that cause apoptosis from working. This keeps AIM-bound cell types alive. Notably, the maintenance of immune cell viability regulates immunity. As our investigation progressed, we concluded that AIM has two sides when it comes to renal diseases. AIM can modulate renal phagocytosis, expedite the elimination of renal tubular cell fragments, and mitigate tissue injury. AIM can additionally exacerbate the development of renal fibrosis and kidney disease by prolonging inflammation. IgA nephropathy (IgAN) may also worsen faster if more protein is in the urine. This is because IgA and immunoglobulin M are found together and expressed. In the review, we provide a comprehensive overview of prior research and concentrate on the impacts of AIM on diverse subcategories of nephropathies. We discovered that AIM is closely associated with renal diseases by playing a positive or negative role in the onset, progression, or cure of kidney disease. AIM is thus a potentially effective therapeutic target for kidney diseases.
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Affiliation(s)
- Yixia Cao
- School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
- Department of Nephrology, Sichuan Academy of Medical Science and Sichuan Provincial People's Hospital, Sichuan Renal Disease Clinical Research Center, University of Electronic Science and Technology of China, Chengdu, China
- Chinese Academy of Sciences Sichuan Translational Medicine Research Hospital, Chengdu, China
| | - Boyan Hu
- School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
- Department of Nephrology, Sichuan Academy of Medical Science and Sichuan Provincial People's Hospital, Sichuan Renal Disease Clinical Research Center, University of Electronic Science and Technology of China, Chengdu, China
- Chinese Academy of Sciences Sichuan Translational Medicine Research Hospital, Chengdu, China
| | - Yunhe Fan
- Reproductive & Women-Children Hospital, School of Medical and Life Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Wei Wang
- Department of Nephrology, Sichuan Academy of Medical Science and Sichuan Provincial People's Hospital, Sichuan Renal Disease Clinical Research Center, University of Electronic Science and Technology of China, Chengdu, China
- Chinese Academy of Sciences Sichuan Translational Medicine Research Hospital, Chengdu, China
| | - Mingxuan Chi
- Department of Nephrology, Sichuan Academy of Medical Science and Sichuan Provincial People's Hospital, Sichuan Renal Disease Clinical Research Center, University of Electronic Science and Technology of China, Chengdu, China
- Chinese Academy of Sciences Sichuan Translational Medicine Research Hospital, Chengdu, China
| | - Moussa Ide Nasser
- Department of Cardiac Surgery, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Guangdong Cardiovascular Institute, Southern Medical University, Guangzhou, 510100, Guangdong, China.
| | - Kuai Ma
- Department of Nephrology, Osaka University Graduate School of Medicine, Osaka, Japan.
| | - Chi Liu
- Department of Nephrology, Sichuan Academy of Medical Science and Sichuan Provincial People's Hospital, Sichuan Renal Disease Clinical Research Center, University of Electronic Science and Technology of China, Chengdu, China.
- Chinese Academy of Sciences Sichuan Translational Medicine Research Hospital, Chengdu, China.
- Renal Department and Nephrology Institute, School of Medicine, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Sichuan Clinical Research Center for Kidney Diseases, Chengdu, China.
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Yasuda K, Shimodan S, Maehara N, Hirota A, Iijima R, Nishijima A, Mori H, Toyama R, Ito A, Yoshikawa Y, Arai S, Miyazaki T. AIM/CD5L ameliorates autoimmune arthritis by promoting removal of inflammatory DAMPs at the lesions. J Autoimmun 2024; 142:103149. [PMID: 38006711 DOI: 10.1016/j.jaut.2023.103149] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2023] [Revised: 10/31/2023] [Accepted: 11/13/2023] [Indexed: 11/27/2023]
Abstract
The hallmark of autoimmune arthritis is the preceding autoantibody production and the following synovial inflammation with hyperplasia and tissue destruction of the joints. The joint inflammation is mediated not only by effector lymphocytes and auto-antibodies but also chronic activation of innate immunity, particularly promoted by the danger-associated molecular patterns (DAMPs). Here we show that apoptosis inhibitor of macrophage (AIM, also called CD5L) protein regulates arthritis by promoting removal of lesional DAMPs both physiologically and therapeutically. When the autoimmune arthritis was promoted by injecting a cocktail of anti-collagen antibodies without type-II collagen immunization, AIM-deficient (AIM-/-) mice exhibited more exacerbated and sustained swelling at multiple joints with greater synovial hyperplasia and bone erosion than wild-type mice. Administration of recombinant AIM (rAIM) reduced S100A8/9, a major DAMP known to be involved in arthritis progression, and decreased various inflammatory cytokines at the lesions in antibody-injected AIM-/- mice, leading to marked prevention of arthritis symptoms. In human rheumatoid arthritis (RA) patients, AIM was more activated via dissociating from IgM-pentamer in response to DAMPs-mediated inflammation both in serum and synovial fluid than in healthy individuals or non-autoimmune osteoarthritis patients, suggesting a disease-regulatory potency of AIM also in human RA patients. Thus, our study implied a therapeutic availability of rAIM to prevent arthritis symptoms targeting DAMPs.
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Affiliation(s)
- Keisuke Yasuda
- The Institute for AIM Medicine, Tokyo, 162-8666, Japan; Laboratory of Molecular Biomedicine for Pathogenesis, Center for Disease Biology and Integrative Medicine, Faculty of Medicine, The University of Tokyo, Tokyo, 113-0033, Japan
| | - Shieri Shimodan
- Laboratory of Molecular Biomedicine for Pathogenesis, Center for Disease Biology and Integrative Medicine, Faculty of Medicine, The University of Tokyo, Tokyo, 113-0033, Japan
| | | | - Aika Hirota
- The Institute for AIM Medicine, Tokyo, 162-8666, Japan
| | - Ruka Iijima
- The Institute for AIM Medicine, Tokyo, 162-8666, Japan
| | | | - Haruka Mori
- The Institute for AIM Medicine, Tokyo, 162-8666, Japan
| | - Ran Toyama
- The Institute for AIM Medicine, Tokyo, 162-8666, Japan
| | - Atsumi Ito
- The Institute for AIM Medicine, Tokyo, 162-8666, Japan
| | | | - Satoko Arai
- The Institute for AIM Medicine, Tokyo, 162-8666, Japan; Laboratory of Molecular Biomedicine for Pathogenesis, Center for Disease Biology and Integrative Medicine, Faculty of Medicine, The University of Tokyo, Tokyo, 113-0033, Japan.
| | - Toru Miyazaki
- The Institute for AIM Medicine, Tokyo, 162-8666, Japan; Laboratoire d'ImmunoRhumatologie Moléculaire, Plateforme GENOMAX, Institut National de la Santé et de la Recherche Médicale UMR_S 1109, Faculté de Médecine, Fédération Hospitalo-Universitaire OMICARE, Fédération de Médecine Translationnelle de Strasbourg, Laboratory of Excellence TRANSPLANTEX, Université de Strasbourg, Strasbourg, France; LEAP, Japan Agency for Medical Research and Development, Tokyo, 113-0033, Japan.
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Takimoto-Sato M, Suzuki M, Kimura H, Ge H, Matsumoto M, Makita H, Arai S, Miyazaki T, Nishimura M, Konno S. Apoptosis inhibitor of macrophage (AIM)/CD5L is involved in the pathogenesis of COPD. Respir Res 2023; 24:201. [PMID: 37592330 PMCID: PMC10433671 DOI: 10.1186/s12931-023-02508-0] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2023] [Accepted: 08/08/2023] [Indexed: 08/19/2023] Open
Abstract
BACKGROUND Alveolar macrophages (AMs) and AM-produced matrix metalloprotease (MMP)-12 are known to play critical roles in the pathogenesis of chronic obstructive pulmonary disease (COPD). The apoptosis inhibitor of the macrophages (AIM)/CD5 molecule-like (CD5L) is a multifunctional protein secreted by the macrophages that mainly exists in the blood in a combined form with the immunoglobulin (Ig)M pentamer. Although AIM has both facilitative and suppressive roles in various diseases, its role in COPD remains unclear. METHODS We investigated the role of AIM in COPD pathogenesis using porcine pancreas elastase (PPE)-induced and cigarette smoke-induced emphysema mouse models and an in vitro model using AMs. We also analyzed the differences in the blood AIM/IgM ratio among nonsmokers, healthy smokers, and patients with COPD and investigated the association between the blood AIM/IgM ratio and COPD exacerbations and mortality in patients with COPD. RESULTS Emphysema formation, inflammation, and cell death in the lungs were attenuated in AIM-/- mice compared with wild-type (WT) mice in both PPE- and cigarette smoke-induced emphysema models. The PPE-induced increase in MMP-12 was attenuated in AIM-/- mice at both the mRNA and protein levels. According to in vitro experiments using AMs stimulated with cigarette smoke extract, the MMP-12 level was decreased in AIM-/- mice compared with WT mice. This decrease was reversed by the addition of recombinant AIM. Furthermore, an analysis of clinical samples showed that patients with COPD had a higher blood AIM/IgM ratio than healthy smokers. Additionally, the blood AIM/IgM ratio was positively associated with disease severity in patients with COPD. A higher AIM/IgM ratio was also associated with a shorter time to the first COPD exacerbation and higher all-cause and respiratory mortality. CONCLUSIONS AIM facilitates the development of COPD by upregulating MMP-12. Additionally, a higher blood AIM/IgM ratio was associated with poor prognosis in patients with COPD. TRIAL REGISTRATION This clinical study, which included nonsmokers, healthy smokers, and smokers with COPD, was approved by the Ethics Committee of the Hokkaido University Hospital (012-0075, date of registration: September 5, 2012). The Hokkaido COPD cohort study was approved by the Ethics Committee of the Hokkaido University School of Medicine (med02-001, date of registration: December 25, 2002).
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Affiliation(s)
- Michiko Takimoto-Sato
- Department of Respiratory Medicine, Faculty of Medicine, Graduate School of Medicine, Hokkaido University, North 15 West 7, Kita-ku, Sapporo, 060-8638, Japan
| | - Masaru Suzuki
- Department of Respiratory Medicine, Faculty of Medicine, Graduate School of Medicine, Hokkaido University, North 15 West 7, Kita-ku, Sapporo, 060-8638, Japan.
| | - Hiroki Kimura
- Department of Respiratory Medicine, Faculty of Medicine, Graduate School of Medicine, Hokkaido University, North 15 West 7, Kita-ku, Sapporo, 060-8638, Japan
- Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, United States of America
| | - Haiyan Ge
- Department of Respiratory and Critical Care Medicine, Huadong Hospital, Fudan University, Shanghai, China
| | - Munehiro Matsumoto
- Department of Respiratory Medicine, Faculty of Medicine, Graduate School of Medicine, Hokkaido University, North 15 West 7, Kita-ku, Sapporo, 060-8638, Japan
| | - Hironi Makita
- Hokkaido Medical Research Institute of Respiratory Diseases, Sapporo, Japan
| | - Satoko Arai
- Laboratory of Molecular Biomedicine for Pathogenesis, Center for Disease Biology and Integrative Medicine, Faculty of Medicine, University of Tokyo, Tokyo, Japan
- The Institute for AIM Medicine, Tokyo, Japan
| | - Toru Miyazaki
- The Institute for AIM Medicine, Tokyo, Japan
- LEAP, Japan Agency for Medical Research and Development, Tokyo, Japan
| | - Masaharu Nishimura
- Department of Respiratory Medicine, Faculty of Medicine, Graduate School of Medicine, Hokkaido University, North 15 West 7, Kita-ku, Sapporo, 060-8638, Japan
- Hokkaido Medical Research Institute of Respiratory Diseases, Sapporo, Japan
| | - Satoshi Konno
- Department of Respiratory Medicine, Faculty of Medicine, Graduate School of Medicine, Hokkaido University, North 15 West 7, Kita-ku, Sapporo, 060-8638, Japan
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Li H, Liu H, Yan LJ, Ding ZN, Zhang X, Pan GQ, Han CL, Tian BW, Tan SY, Dong ZR, Wang DX, Yan YC, Li T. Performance of GALAD score and serum biomarkers for detecting NAFLD-related HCC: a systematic review and network meta-analysis. Expert Rev Gastroenterol Hepatol 2023; 17:1159-1167. [PMID: 37929312 DOI: 10.1080/17474124.2023.2279175] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/14/2023] [Accepted: 10/31/2023] [Indexed: 11/07/2023]
Abstract
INTRODUCTION The incidence of nonalcoholic fatty liver disease (NAFLD)-related hepatocellular carcinoma (HCC) is increasing globally. We aimed to assess the performance of alpha-fetoprotein (AFP), AFP-L3, des-gamma-carboxy prothrombin (DCP), and GALAD score in detecting NAFLD-related HCC. METHODS We searched the relevant literature in PubMed, Embase and Cochrane. Conventional and network meta-analyses were performed for sensitivity, specificity, Youden index (YI), and the area under the summary receiver operator characteristic curve (AUC). RESULTS Fifteen studies involving 2031 NAFLD participants were included in this meta-analysis. When detecting early-stage NAFLD-related HCC, GALAD score and DCP process excellent performance. The sensitivity and AUC of DCP (0.60, 0.74, respectively) were higher than AFP (0.34, 0.59, respectively). The network meta-analysis showed that DCP and GALAD score had similar performance. In detecting all-stage NAFLD-related HCC, GALAD score (sensitivity = 0.87; YI = 0.77) performed better than AFP (sensitivity = 0.56; YI = 0.50), AFP-L3 (sensitivity = 0.39; YI = 0.36) and DCP (sensitivity = 0.73; YI = 0.62). Network meta-analysis obtained consistent results with conventional meta-analysis. CONCLUSIONS Due to the lower cost-effectiveness, DCP was more suitable for detecting early NAFLD-related HCC. AFP could be used in detecting all-stage NAFLD-related HCC.
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Affiliation(s)
- Han Li
- Department of General Surgery, Qilu Hospital of Shandong University, Jinan, China
| | - Hui Liu
- Department of General Surgery, Qilu Hospital of Shandong University, Jinan, China
| | - Lun-Jie Yan
- Department of General Surgery, Qilu Hospital of Shandong University, Jinan, China
| | - Zi-Niu Ding
- Department of General Surgery, Qilu Hospital of Shandong University, Jinan, China
| | - Xiao Zhang
- Department of General Surgery, Qilu Hospital of Shandong University, Jinan, China
| | - Guo-Qiang Pan
- Department of General Surgery, Qilu Hospital of Shandong University, Jinan, China
| | - Cheng-Long Han
- Department of General Surgery, Qilu Hospital of Shandong University, Jinan, China
| | - Bao-Wen Tian
- Department of General Surgery, Qilu Hospital of Shandong University, Jinan, China
| | - Si-Yu Tan
- Department of General Surgery, Qilu Hospital of Shandong University, Jinan, China
| | - Zhao-Ru Dong
- Department of General Surgery, Qilu Hospital of Shandong University, Jinan, China
| | - Dong-Xu Wang
- Department of General Surgery, Qilu Hospital of Shandong University, Jinan, China
| | - Yu-Chuan Yan
- Department of General Surgery, Qilu Hospital of Shandong University, Jinan, China
| | - Tao Li
- Department of General Surgery, Qilu Hospital of Shandong University, Jinan, China
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9
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Gao Z, Wu X, Yang L, Liu C, Wang X, Wang H, Dong K. Role of CD5 molecular-like on hepatocellular carcinoma. Chin Med J (Engl) 2023; 136:556-564. [PMID: 36939243 PMCID: PMC10106147 DOI: 10.1097/cm9.0000000000002576] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2022] [Indexed: 03/21/2023] Open
Abstract
BACKGROUND CD5L (CD5 molecular-like) plays an important role in lipid metabolism and immune regulation. This study aimed to investigate the roles of CD5L on liver hepatocellular carcinoma (LIHC). METHODS We analyzed the CD5L mRNA expression and its potential prognostic value based on The Cancer Genome Atlas and Gene Expression Omnibus databases. Immunohistochemical analysis was used to investigate the CD5L levels in LIHC tissues. Serum CD5L levels in LIHC were detected by enzyme-linked immunosorbent assay. Cell Counting Kit-8 (CCK-8) assay was used to investigate the effect of CD5L treatment on HepG2 and QSG-7701 cell proliferation. CD5L expression correlated genes were exhumed based on the LinkedOmics. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses for CD5L associated genes were performed. The correlation between CD5L and tumor immune infiltration was analyzed by using Tumor Immune Estimation Resource (TIMER) 2.0. RESULTS CD5L mRNA and protein levels were significantly decreased in LIHC tumor tissue compared with non-tumor control tissues. Moreover, serum CD5L levels were significantly lower in LIHC patients than that in healthy subjects. Gene Expression Profiling Interactive Analysis 2 and Kaplan-Meier plotter analysis showed that a high-CD5L expression was correlated with favorable overall survival in LIHC patients, except the LIHC patients with hepatitis virus. CCK-8 results showed that CD5L treatment significantly decreased HepG2 cell proliferation in a concentration-dependent manner, and CD5L treatment had no effect on the proliferation of non-tumor hepatocyte line QSG-7701. CD5L associated genes were enriched in the immune response biological process, and CD5L expression levels were positively correlated with the immune infiltrates of CD8 + T cell and M1 macrophage cells but negatively correlated with CD4 + T cells and M0 macrophage cell infiltration. CONCLUSIONS Exogenous CD5L inhibits cell proliferation of hepatocellular carcinoma. CD5L may act as a role of prognostic marker.
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Affiliation(s)
- Zhaowei Gao
- Department of Clinical Laboratory, Tangdu Hospital, Air Force Medical University, Xi’an, Shaanxi 710038, China
| | - Xianan Wu
- Department of Medical Laboratory, Tangdu Hospital, Air Force Military Medical University, Xi’an, Shaanxi 710038, China
| | - Lan Yang
- Department of Clinical Laboratory, Tangdu Hospital, Air Force Medical University, Xi’an, Shaanxi 710038, China
| | - Chong Liu
- Department of Medical Laboratory, Tangdu Hospital, Air Force Military Medical University, Xi’an, Shaanxi 710038, China
| | - Xi Wang
- Department of Clinical Laboratory, Tangdu Hospital, Air Force Medical University, Xi’an, Shaanxi 710038, China
| | - Huiping Wang
- Department of Clinical Laboratory, Tangdu Hospital, Air Force Medical University, Xi’an, Shaanxi 710038, China
| | - Ke Dong
- Department of Clinical Laboratory, Tangdu Hospital, Air Force Medical University, Xi’an, Shaanxi 710038, China
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10
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Ueno M, Takeda H, Takai A, Seno H. Risk factors and diagnostic biomarkers for nonalcoholic fatty liver disease-associated hepatocellular carcinoma: Current evidence and future perspectives. World J Gastroenterol 2022; 28:3410-3421. [PMID: 36158261 PMCID: PMC9346451 DOI: 10.3748/wjg.v28.i27.3410] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/02/2022] [Revised: 04/24/2022] [Accepted: 06/16/2022] [Indexed: 02/06/2023] Open
Abstract
High rates of excessive calorie intake diets and sedentary lifestyles have led to a global increase in nonalcoholic fatty liver disease (NAFLD). As a result, this condition has recently become one of the leading causes of hepatocellular carcinoma (HCC). Furthermore, the incidence of NAFLD-associated HCC (NAFLD-HCC) is expected to increase in the near future. Advanced liver fibrosis is the most common risk factor for NAFLD-HCC. However, up to 50% of NAFLD-HCC cases develop without underlying liver cirrhosis. Epidemiological studies have revealed many other risk factors for this condition; including diabetes, other metabolic traits, obesity, old age, male sex, Hispanic ethnicity, mild alcohol intake, and elevated liver enzymes. Specific gene variants, such as single-nucleotide polymorphisms of patatin-like phospholipase domain 3, transmembrane 6 superfamily member 2, and membrane-bound O-acyl-transferase domain-containing 7, are also associated with an increased risk of HCC in patients with NAFLD. This clinical and genetic information should be interpreted together for accurate risk prediction. Alpha-fetoprotein (AFP) is the only biomarker currently recommended for HCC screening. However, it is not sufficiently sensitive in addressing this diagnostic challenge. The GALAD score can be calculated based on sex, age, lectin-bound AFP, AFP, and des-carboxyprothrombin and is reported to show better diagnostic performance for HCC. In addition, emerging studies on genetic and epigenetic biomarkers have also yielded promising diagnostic potential. However, further research is needed to establish an effective surveillance program for the early diagnosis of NAFLD-HCC.
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Affiliation(s)
- Masayuki Ueno
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto 6068507, Japan
| | - Haruhiko Takeda
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto 6068507, Japan
| | - Atsushi Takai
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto 6068507, Japan
| | - Hiroshi Seno
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto 6068507, Japan
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