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Annadurai P, Isaac AE. Unveiling the role of IL7R in metabolism-associated fatty liver disease leading to hepatocellular carcinoma through transcriptomic and machine learning approaches. Discov Oncol 2025; 16:873. [PMID: 40408005 PMCID: PMC12102058 DOI: 10.1007/s12672-025-02638-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/23/2025] [Accepted: 05/09/2025] [Indexed: 05/26/2025] Open
Abstract
Dysregulation of hepatic metabolism is a crucial factor in the development of fatty liver disease and significantly increases the risk of hepatocellular carcinoma (HCC). This study aims to identify the genes implicated in the prognosis of HCC among individuals suffering from metabolic fatty liver disease. We analysed protein-protein interaction (PPI) networks and constructed a weighted gene co-expression network analysis (WGCNA) using high-throughput gene expression profiling datasets. Our meta-analysis uncovered 442 differentially expressed genes (DEGs), comprising 30 upregulated and 412 downregulated genes. We constructed a PPI network from the DEGs and identified significant hub genes based on their degree centrality scores. Additionally, WGCNA highlighted impactful genes and tightly correlated modules, leading to the creation of a gene interaction network specific to metabolism-associated fatty liver disease (MAFLD). Pathway analysis revealed the candidate regulatory gene interleukin-7 receptor (IL7R), which is involved in cytokine-mediated signalling across both interaction networks. Pro-inflammatory cytokines interact with IL7R, activating the JAK/STAT pathway that influences gene expression throughout progression to HCC. IL7R activates STAT3, affecting the behaviour of activated hepatic stellate cells following initial liver damage. Furthermore, the expression of the IL7R gene was validated as a predictor of HCC malignancy through a logistic regression model, resulting in an accuracy of 92%. Findings suggest that IL7R could be the target gene associated with metabolism-linked HCC. It could significantly impact the management of metabolic-associated fatty liver disease (MAFLD) and may help enhance HCC diagnostics to improve patient outcomes.
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Affiliation(s)
- Priyadharshini Annadurai
- Bioinformatics Programming Laboratory, Department of Bioscience, School of Bio Science and Technology, Vellore Institute of Technology, Katpadi, Vellore - 632014, Tamil Nadu, India
| | - Arnold Emerson Isaac
- Bioinformatics Programming Laboratory, Department of Bioscience, School of Bio Science and Technology, Vellore Institute of Technology, Katpadi, Vellore - 632014, Tamil Nadu, India.
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German-Cortés J, Herrero R, Torroglosa N, Pumarola A, Fischer-Albiol N, Campos-Moreno S, Sabaté S, Alcina À, Mancilla S, García B, Llaguno-Munive M, Díaz-Riascos ZV, Martins C, Schwartz S, Ferrer-Costa R, Abasolo I, Sánchez-Gómez P, Sarmento B, Rafael D, Andrade F. Preclinical evaluation of several polymeric micelles identifies Soluplus®-docetaxel as the most effective candidate in multiple glioblastoma models. J Control Release 2025; 381:113616. [PMID: 40073942 DOI: 10.1016/j.jconrel.2025.113616] [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: 11/10/2024] [Revised: 01/23/2025] [Accepted: 03/07/2025] [Indexed: 03/14/2025]
Abstract
Glioblastoma multiforme (GBM) is one of the most lethal cancers, with limited treatment options due to the blood-brain barrier (BBB), systemic toxicity, and treatment resistance. Nanomedicine offers potential solutions to these challenges. This study explores Pluronic® F127 and Soluplus®-based micelles as carriers for Lomustine, Gefitinib, and Docetaxel to determine the optimal system for GBM therapy. Micelles were physicochemically characterized and biologically validated using U87-MG and U251-MG GBM cell lines in 2D and 3D models, assessing internalization, safety, and therapeutic efficacy. Soluplus® micelles (SM) showed favorable properties for intravenous administration, including low polydispersity, efficient drug release in the tumoral microenvironment, minimal cell toxicity, and a BBB-crossing rate of 15 %. Among the drugs tested, Docetaxel showed the lowest IC50 values in both 2D cell models and demonstrated superior efficacy in 3D cultures when delivered by SM. Molecular analysis confirmed that SM-D impacts key GBM-related pathways, affecting markers like E-cadherin, EPCAM, L1CAM, or EGFR. In vivo, SM-D significantly reduced tumor mass and cancer cell density, showing a favorable safety profile compared to free Docetaxel, as evidenced by reduced weight loss and histological assessments. Overall, SM-D stands out as the most promising approach for GBM treatment, supporting the potential of nanomedicine in overcoming the barriers to effective glioblastoma therapy.
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Affiliation(s)
- Júlia German-Cortés
- Clinical Biochemistry, Drug Delivery and Therapy Group (CB-DDT), Vall d'Hebron Institut of Research (VHIR), Vall d'Hebron University Hospital, Vall d'Hebron Barcelona Hospital Campus, Passeig de la Vall d'Hebron, 119-129, 08035 Barcelona, Spain; Doctoral program in Biotechnology, Faculty of Pharmacy and Food Sciences, School of Pharmacy, Universitat de Barcelona (UB), Av. de Joan XXIII, 27-31, 08028 Barcelona, Spain
| | - Raquel Herrero
- Clinical Biochemistry, Drug Delivery and Therapy Group (CB-DDT), Vall d'Hebron Institut of Research (VHIR), Vall d'Hebron University Hospital, Vall d'Hebron Barcelona Hospital Campus, Passeig de la Vall d'Hebron, 119-129, 08035 Barcelona, Spain
| | - Natalia Torroglosa
- Clinical Biochemistry, Drug Delivery and Therapy Group (CB-DDT), Vall d'Hebron Institut of Research (VHIR), Vall d'Hebron University Hospital, Vall d'Hebron Barcelona Hospital Campus, Passeig de la Vall d'Hebron, 119-129, 08035 Barcelona, Spain
| | - Alexandra Pumarola
- Clinical Biochemistry, Drug Delivery and Therapy Group (CB-DDT), Vall d'Hebron Institut of Research (VHIR), Vall d'Hebron University Hospital, Vall d'Hebron Barcelona Hospital Campus, Passeig de la Vall d'Hebron, 119-129, 08035 Barcelona, Spain
| | - Narine Fischer-Albiol
- Clinical Biochemistry, Drug Delivery and Therapy Group (CB-DDT), Vall d'Hebron Institut of Research (VHIR), Vall d'Hebron University Hospital, Vall d'Hebron Barcelona Hospital Campus, Passeig de la Vall d'Hebron, 119-129, 08035 Barcelona, Spain
| | - Sofia Campos-Moreno
- Clinical Biochemistry, Drug Delivery and Therapy Group (CB-DDT), Vall d'Hebron Institut of Research (VHIR), Vall d'Hebron University Hospital, Vall d'Hebron Barcelona Hospital Campus, Passeig de la Vall d'Hebron, 119-129, 08035 Barcelona, Spain
| | - Sofia Sabaté
- Clinical Biochemistry, Drug Delivery and Therapy Group (CB-DDT), Vall d'Hebron Institut of Research (VHIR), Vall d'Hebron University Hospital, Vall d'Hebron Barcelona Hospital Campus, Passeig de la Vall d'Hebron, 119-129, 08035 Barcelona, Spain
| | - Àngels Alcina
- Clinical Biochemistry, Drug Delivery and Therapy Group (CB-DDT), Vall d'Hebron Institut of Research (VHIR), Vall d'Hebron University Hospital, Vall d'Hebron Barcelona Hospital Campus, Passeig de la Vall d'Hebron, 119-129, 08035 Barcelona, Spain; Functional Validation & Preclinical Research (FVPR)/U20 ICTS Nanbiosis, Vall d'Hebron Institut de Recerca (VHIR), Universitat Autònoma de Barcelona (UAB), 08035 Barcelona, Spain
| | - Sandra Mancilla
- Clinical Biochemistry, Drug Delivery and Therapy Group (CB-DDT), Vall d'Hebron Institut of Research (VHIR), Vall d'Hebron University Hospital, Vall d'Hebron Barcelona Hospital Campus, Passeig de la Vall d'Hebron, 119-129, 08035 Barcelona, Spain; Functional Validation & Preclinical Research (FVPR)/U20 ICTS Nanbiosis, Vall d'Hebron Institut de Recerca (VHIR), Universitat Autònoma de Barcelona (UAB), 08035 Barcelona, Spain; Centro de Investigación Biomédica en Red de Bioingenería, Biomateriales y Nanomedicina (CIBER-BBN), Instituto De Salud Carlos III, Barcelona, Spain
| | - Belén García
- Clinical Biochemistry, Drug Delivery and Therapy Group (CB-DDT), Vall d'Hebron Institut of Research (VHIR), Vall d'Hebron University Hospital, Vall d'Hebron Barcelona Hospital Campus, Passeig de la Vall d'Hebron, 119-129, 08035 Barcelona, Spain; Functional Validation & Preclinical Research (FVPR)/U20 ICTS Nanbiosis, Vall d'Hebron Institut de Recerca (VHIR), Universitat Autònoma de Barcelona (UAB), 08035 Barcelona, Spain; Centro de Investigación Biomédica en Red de Bioingenería, Biomateriales y Nanomedicina (CIBER-BBN), Instituto De Salud Carlos III, Barcelona, Spain
| | - Monserrat Llaguno-Munive
- Laboratorio de Física Médica, Subdirección de Investigación Básica, Instituto Nacional de Cancerología, Av. San Fernando 22, 14080 Ciudad de México, CDMX, Mexico
| | - Zamira V Díaz-Riascos
- Clinical Biochemistry, Drug Delivery and Therapy Group (CB-DDT), Vall d'Hebron Institut of Research (VHIR), Vall d'Hebron University Hospital, Vall d'Hebron Barcelona Hospital Campus, Passeig de la Vall d'Hebron, 119-129, 08035 Barcelona, Spain; Functional Validation & Preclinical Research (FVPR)/U20 ICTS Nanbiosis, Vall d'Hebron Institut de Recerca (VHIR), Universitat Autònoma de Barcelona (UAB), 08035 Barcelona, Spain; Centro de Investigación Biomédica en Red de Bioingenería, Biomateriales y Nanomedicina (CIBER-BBN), Instituto De Salud Carlos III, Barcelona, Spain
| | - Cláudia Martins
- i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Rua Alfredo Allen 208, Porto 4200-135, Portugal; INEB - Instituto de Engenharia Biomédica, Universidade do Porto, Rua Alfredo Allen 208, Porto 4200-135, Portugal
| | - Simó Schwartz
- Clinical Biochemistry, Drug Delivery and Therapy Group (CB-DDT), Vall d'Hebron Institut of Research (VHIR), Vall d'Hebron University Hospital, Vall d'Hebron Barcelona Hospital Campus, Passeig de la Vall d'Hebron, 119-129, 08035 Barcelona, Spain; Clinical Biochemistry Service, Vall d'Hebron University Hospital, Vall d'Hebron Barcelona Hospital Campus, Passeig de la Vall d'Hebron, 119-129, 08035 Barcelona, Spain
| | - Roser Ferrer-Costa
- Clinical Biochemistry, Drug Delivery and Therapy Group (CB-DDT), Vall d'Hebron Institut of Research (VHIR), Vall d'Hebron University Hospital, Vall d'Hebron Barcelona Hospital Campus, Passeig de la Vall d'Hebron, 119-129, 08035 Barcelona, Spain; Clinical Biochemistry Service, Vall d'Hebron University Hospital, Vall d'Hebron Barcelona Hospital Campus, Passeig de la Vall d'Hebron, 119-129, 08035 Barcelona, Spain
| | - Ibane Abasolo
- Clinical Biochemistry, Drug Delivery and Therapy Group (CB-DDT), Vall d'Hebron Institut of Research (VHIR), Vall d'Hebron University Hospital, Vall d'Hebron Barcelona Hospital Campus, Passeig de la Vall d'Hebron, 119-129, 08035 Barcelona, Spain; Functional Validation & Preclinical Research (FVPR)/U20 ICTS Nanbiosis, Vall d'Hebron Institut de Recerca (VHIR), Universitat Autònoma de Barcelona (UAB), 08035 Barcelona, Spain; Centro de Investigación Biomédica en Red de Bioingenería, Biomateriales y Nanomedicina (CIBER-BBN), Instituto De Salud Carlos III, Barcelona, Spain; Clinical Biochemistry Service, Vall d'Hebron University Hospital, Vall d'Hebron Barcelona Hospital Campus, Passeig de la Vall d'Hebron, 119-129, 08035 Barcelona, Spain
| | - Pilar Sánchez-Gómez
- Unidad de Neurobiología Molecular, Área de Biología Celular y del Desarrollo, Instituto de Salud Carlos III, Ctra. Pozuelo-Majadahonda, km 2, 28220 Madrid, Spain
| | - Bruno Sarmento
- i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Rua Alfredo Allen 208, Porto 4200-135, Portugal; INEB - Instituto de Engenharia Biomédica, Universidade do Porto, Rua Alfredo Allen 208, Porto 4200-135, Portugal; IUCS-CESPU, Rua Central de Gandra 1317, Gandra 4585-116, Portugal
| | - Diana Rafael
- Clinical Biochemistry, Drug Delivery and Therapy Group (CB-DDT), Vall d'Hebron Institut of Research (VHIR), Vall d'Hebron University Hospital, Vall d'Hebron Barcelona Hospital Campus, Passeig de la Vall d'Hebron, 119-129, 08035 Barcelona, Spain; Functional Validation & Preclinical Research (FVPR)/U20 ICTS Nanbiosis, Vall d'Hebron Institut de Recerca (VHIR), Universitat Autònoma de Barcelona (UAB), 08035 Barcelona, Spain; Centro de Investigación Biomédica en Red de Bioingenería, Biomateriales y Nanomedicina (CIBER-BBN), Instituto De Salud Carlos III, Barcelona, Spain.
| | - Fernanda Andrade
- Clinical Biochemistry, Drug Delivery and Therapy Group (CB-DDT), Vall d'Hebron Institut of Research (VHIR), Vall d'Hebron University Hospital, Vall d'Hebron Barcelona Hospital Campus, Passeig de la Vall d'Hebron, 119-129, 08035 Barcelona, Spain; Functional Validation & Preclinical Research (FVPR)/U20 ICTS Nanbiosis, Vall d'Hebron Institut de Recerca (VHIR), Universitat Autònoma de Barcelona (UAB), 08035 Barcelona, Spain; Department of Pharmacy and Pharmaceutical Technology and Physicochemistry, Faculty of Pharmacy and Food Sciences, School of Pharmacy, Universitat de Barcelona (UB), Av. de Joan XXIII, 27-31, 08028 Barcelona, Spain.
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Akkus E, Karaosmanoğlu AD, Gülpınar B, Süer E, Ürün Y. Hepatic steatosis development as a long-term complication among testicular germ cell tumor survivors. Future Oncol 2025; 21:983-990. [PMID: 39995254 PMCID: PMC11938976 DOI: 10.1080/14796694.2025.2467613] [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: 01/24/2024] [Accepted: 02/12/2025] [Indexed: 02/26/2025] Open
Abstract
BACKGROUND Hepatic steatosis (HS) development and its risk factors in testicular germ cell tumor (TGCT) survivors have not been investigated. METHODS The study was designed as a retrospective observational study. Patients with existing HS at diagnosis were excluded. Serial imaging was utilized to detect HS. RESULTS A total of 106 TGCT survivors were included. HS developed in 57% (n = 61) during a median follow-up of 51.8 months (8.5-241.5); 77% (n = 47) of those had persistent HS. Patients who developed HS had a higher baseline body mass index (BMI) (median 26.5 vs. 23.6 kg/m2, p = 0.000). Higher baseline BMI [adjusted odds ratio (aOR): 1.35, (95% CI: 1.10-1.65) p = 0.004] and S0 stage [aOR: 3.87, (95% CI: 1.18-12.67), p = 0.025] were associated with a higher risk of HS development. The median time from the diagnosis of TGCT to the detection of HS was 44.7 months (29.5-59.8). Higher baseline BMI was associated with earlier development of HS both in all patients [hazard ratio (HR): 1.16, (95% CI: 1.04-1.30), p = 0.007] and patients treated with the BEP regimen [HR: 1.21, (95% CI: 1.01-1.47), p = 0.038]. CONCLUSION HS may be considered a long-term complication in TGCT patients. The risk is associated with baseline BMI. Diagnosis and management of HS should be implemented in the survivorship care plan of TGCT survivors.
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Affiliation(s)
- Erman Akkus
- Faculty of Medicine, Department of Medical Oncology, Ankara University, Ankara, Türkiye
| | | | - Başak Gülpınar
- Faculty of Medicine, Department of Radiology, Ankara University, Ankara, Türkiye
| | - Evren Süer
- Faculty of Medicine, Department of Urology, Ankara University, Ankara, Türkiye
| | - Yüksel Ürün
- Faculty of Medicine, Department of Medical Oncology, Ankara University, Ankara, Türkiye
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Ali B, Kamani L, Salim A, Alam A, Zuberi BF, Farooqi JI, Naqvi AB, Ali Z, Majid S, Hashmi ZY, Choudhry AA, Salih M, Khan AA, Azam SMZ, Abbas Z, Siddique M, Nawaz AA. HEPNET Position Statement-I, Case Definition, Classification, Screening & Diagnosis of Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) in Pakistan: A Resource for Primary and Secondary Care Physicians. Pak J Med Sci 2025; 41:929-938. [PMID: 40103882 PMCID: PMC11911726 DOI: 10.12669/pjms.41.3.10081] [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: 04/27/2024] [Revised: 09/18/2024] [Accepted: 02/15/2025] [Indexed: 03/20/2025] Open
Abstract
The Hep-Net position paper comes at a significant time in the history of Metabolically Associated Fatty Liver Disease (MAFLD) due to the rapid rise in this disease entity in the past decade. Metabolically Associated Fatty Liver Disease, by its very name, encompasses several common metabolic disease entities, top among those being diabetes and obesity. For Pakistan, the situation is serious as it is among the top 10 countries globally regarding the prevalence of obesity and number one in terms of diabetes, with over a quarter of adults affected. There remains slight ambiguity as regards the nomenclature of MAFLD, with western societies preferring to remove the word "fatty" and substitute with `'steatotic" i.e. MASLD. Regardless of names/titles the metabolic nature of the disease and its management remains the same and fortunately, that is something where universal consensus is present. Under the umbrella of Hep-Net, eminent hepatologists from all over Pakistan have pooled their efforts to formulate guidelines that are specifically tailored to the Pakistani population, its specific lifestyle and relevant interventions that are needed to treat fatty/steatotic liver disease. By virtue of its multi-systemic consequences, metabolic fatty liver disease represents the most significant and expensive disease entity, globally. Prevention, through public education and timely intervention in diagnosed cases will serve to avert a healthcare storm that will far outweigh viral hepatitis.
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Affiliation(s)
- Bushra Ali
- Bushra Ali, Fatima Memorial Hospital College of Medicine and Dentistry, Lahore, Pakistan
| | - Lubna Kamani
- Lubna Kamani, Liaquat National Hospital, National Medical Center, Karachi, Pakistan
| | - Adnan Salim
- Adnan Salim, Shaikh Zayed Medical Complex Lahore, Pakistan
| | - Altaf Alam
- Altaf Alam, Consultant Gastroenterologist, Evercare Hospital Lahore, Lahore, Pakistan
| | | | | | | | - Zeeshan Ali
- Zeeshan Ali, Jinnah Sindh Medical University & Jinnah Postgraduate Medical Center Karachi, Pakistan
| | - Shahid Majid
- Shahid Majid, The Indus Hospital and Health Network, Karachi, Pakistan
| | | | - Asad A Choudhry
- Asad A Choudhry, Consultant Gastroenterologist, Chaudhry Hospital, Gujranwala
| | - Muhammad Salih
- Muhammad Salih, Shifa International Hospital, Islamabad, Pakistan
| | - Anwar Ahmed Khan
- Anwaar Ahmed Khan, Doctors Hospital and Medical Center, Lahore, Pakistan
| | - Syed M. Zahid Azam
- Syed M. Zahid Azam, National Institute of Liver & GI Diseases, Dow University, Karachi, Pakistan
| | - Zaigham Abbas
- Zaigham Abbas, Ziauddin University Hospital Clifton Karachi, Pakistan
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Saad MFS, Abdullah MNH, Lim V, Bahari H, Khoo BY, Tan JJ, Yong YK. Exploring the role of Bisphenol A in obesity-driven colorectal cancer progression: network toxicology and multi-organ pathology in animal models. Toxicol Appl Pharmacol 2025; 495:117227. [PMID: 39788208 DOI: 10.1016/j.taap.2025.117227] [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: 11/15/2024] [Revised: 01/01/2025] [Accepted: 01/05/2025] [Indexed: 01/12/2025]
Abstract
Bisphenol A (BPA), an endocrine disruptor, is linked to cancer progression in estrogen-responsive tissues, but its role in promoting colorectal cancer (CRC) progression in the context of obesity remains underexplored. This study examines BPA's influence on CRC in obese Sprague-Dawley rats using network toxicology and experimental models. Computational analysis using the Database for Annotation, Visualization, and Integrated Discovery identified pathways such as "CRC" and "chemical carcinogenesis-receptor activation", implicating the PI3K-AKT pathway in IL-1 beta upregulation and BPA's role in CRC during obesity. Thirty male rats were grouped (n = 6) as follows: N (normal diet), NC (normal diet + CRC), HC (high-fat diet + CRC), NCB (normal diet + CRC + BPA), and HCB (high-fat diet + CRC + BPA). CRC was induced with 1,2-dimethylhydrazine (40 mg/kg), and BPA (25 mg/kg) was administered for 19 weeks. Although BPA exposure did not affect body weight or biochemical parameters, the HCB group exhibited significant histopathological changes in the colon, including lymphoid hyperplasia, liver damage, and increased IL-1β levels. Furthermore, diet influenced adipocyte size, exacerbating BPA's effects on CRC progression. Findings suggest BPA may worsen CRC progression in obese rats through identified pathways, promoting multi-organ pathology and underscoring the need for stricter regulations, especially for vulnerable populations. ENVIRONMENTAL IMPLICATION: Bisphenol A (BPA), a widespread environmental contaminant, is increasingly linked to serious health issues, including cancer, in susceptible populations. Our study highlights BPA's role in promoting obesity-driven colorectal cancer (CRC) progression, demonstrating its carcinogenic potential in high-risk contexts. These findings emphasize the urgent need for regulatory scrutiny of BPA exposure, particularly in obese individuals, and support the development of safer alternatives. Addressing BPA's impact can contribute to preventive health strategies and inform policies aimed at reducing environmental and public health risks associated with endocrine-disrupting chemicals.
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Affiliation(s)
- Muhamad Fikri Shazlan Saad
- Department of Human Anatomy, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, 43400 UPM Serdang, Selangor, Malaysia
| | - Muhammad Nazrul Hakim Abdullah
- Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, 43400 UPM Serdang, Selangor, Malaysia
| | - Vuanghao Lim
- Advanced Medical and Dental Institute, Universiti Sains Malaysia, Bertam 13200, Kepala Batas, Penang, Malaysia
| | - Hasnah Bahari
- Department of Human Anatomy, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, 43400 UPM Serdang, Selangor, Malaysia
| | - Boon Yin Khoo
- Institute for Research in Molecular Medicine, Universiti Sains Malaysia, 11800 USM, Penang, Malaysia
| | - Jun Jie Tan
- Advanced Medical and Dental Institute, Universiti Sains Malaysia, Bertam 13200, Kepala Batas, Penang, Malaysia.
| | - Yoke Keong Yong
- Department of Human Anatomy, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, 43400 UPM Serdang, Selangor, Malaysia.
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Werner W, Kuzminskaya M, Lurje I, Tacke F, Hammerich L. Overcoming Resistance to Immune Checkpoint Blockade in Liver Cancer with Combination Therapy: Stronger Together? Semin Liver Dis 2024; 44:159-179. [PMID: 38806159 PMCID: PMC11245330 DOI: 10.1055/a-2334-8311] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 05/30/2024]
Abstract
Primary liver cancer, represented mainly by hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (CCA), is one of the most common and deadliest tumors worldwide. While surgical resection or liver transplantation are the best option in early disease stages, these tumors often present in advanced stages and systemic treatment is required to improve survival time. The emergence of immune checkpoint inhibitor (ICI) therapy has had a positive impact especially on the treatment of advanced cancers, thereby establishing immunotherapy as part of first-line treatment in HCC and CCA. Nevertheless, low response rates reflect on the usually cold or immunosuppressed tumor microenvironment of primary liver cancer. In this review, we aim to summarize mechanisms of resistance leading to tumor immune escape with a special focus on the composition of tumor microenvironment in both HCC and CCA, also reflecting on recent important developments in ICI combination therapy. Furthermore, we discuss how combination of ICIs with established primary liver cancer treatments (e.g. multikinase inhibitors and chemotherapy) as well as more complex combinations with state-of-the-art therapeutic concepts may reshape the tumor microenvironment, leading to higher response rates and long-lasting antitumor immunity for primary liver cancer patients.
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Affiliation(s)
- Wiebke Werner
- Department of Hepatology and Gastroenterology, Charité Universitaetsmedizin Berlin, Berlin, Germany
| | - Maria Kuzminskaya
- Department of Hepatology and Gastroenterology, Charité Universitaetsmedizin Berlin, Berlin, Germany
| | - Isabella Lurje
- Department of Hepatology and Gastroenterology, Charité Universitaetsmedizin Berlin, Berlin, Germany
| | - Frank Tacke
- Department of Hepatology and Gastroenterology, Charité Universitaetsmedizin Berlin, Berlin, Germany
| | - Linda Hammerich
- Department of Hepatology and Gastroenterology, Charité Universitaetsmedizin Berlin, Berlin, Germany
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Wójcik M, Grabowski S, Jarosz ŁS, Szymczak B, Longo V, della Croce CM, Hejdysz M, Cieślak A, Gruszczyński K, Marek A. Liver Antioxidant Capacity and Steatosis in Laying Hens Exposed to Various Quantities of Lupin ( Lupinus angustifolius) Seeds in the Diet. Antioxidants (Basel) 2024; 13:251. [PMID: 38397849 PMCID: PMC10886069 DOI: 10.3390/antiox13020251] [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: 01/08/2024] [Revised: 02/14/2024] [Accepted: 02/15/2024] [Indexed: 02/25/2024] Open
Abstract
Despite the many beneficial properties of legume plants, their use in diets for poultry is limited by the presence of antinutritional factors. The aim of the study was to determine the activity of DT-diaphorase, ethoxycoumarin O-deethylase, and catalase, and the concentration of malondialdehyde in liver tissue, as well as the activity of SOD and CAT in the serum of Hy-line Brown hens fed a diet supplemented with various doses of Lupinus angustifolius seeds. The results indicate that the use of large amounts of lupin in the diet resulted in an increase in MDA concentration in the liver and the lipid vacuolization of hepatocytes. A significant increase in DTD activity was observed in chickens receiving 15% lupin. Regardless of lupin dose, no increase in SOD activity was observed in chicken serum after 33 days of the experiment. From the 66th day of the experiment, an increase in catalase activity in the serum of laying hens was observed, while low activity of this enzyme was found in the liver. It can be concluded that the short-term use of lupin in the diet of laying hens does not affect the activity of antioxidant enzymes and, therefore, does not affect the oxidative-antioxidant balance of their body.
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Affiliation(s)
- Marta Wójcik
- Sub-Department of Pathophysiology, Department of Preclinical of Veterinary Sciences, Faculty of Veterinary Medicine, University of Life Sciences in Lublin, Akademicka 12, 20-033 Lublin, Poland; (M.W.); (B.S.); (K.G.)
| | - Sebastian Grabowski
- Department of Epizootiology and Clinic of Infectious Diseases, Faculty of Veterinary Medicine, University of Life Sciences in Lublin, Głęboka 30, 20-612 Lublin, Poland;
| | - Łukasz S. Jarosz
- Department of Epizootiology and Clinic of Infectious Diseases, Faculty of Veterinary Medicine, University of Life Sciences in Lublin, Głęboka 30, 20-612 Lublin, Poland;
| | - Bartłomiej Szymczak
- Sub-Department of Pathophysiology, Department of Preclinical of Veterinary Sciences, Faculty of Veterinary Medicine, University of Life Sciences in Lublin, Akademicka 12, 20-033 Lublin, Poland; (M.W.); (B.S.); (K.G.)
| | - Vincenzo Longo
- Institute of Agricultural Biology and Biotechnology, National Research Council (CNR), Via Moruzzi 1, 56124 Pisa, Italy; (V.L.); (C.M.d.C.)
| | - Clara Maria della Croce
- Institute of Agricultural Biology and Biotechnology, National Research Council (CNR), Via Moruzzi 1, 56124 Pisa, Italy; (V.L.); (C.M.d.C.)
| | - Marcin Hejdysz
- Department of Animal Breeding and Product Quality Assessment, Poznań University of Life Sciences, Wołynska 33, 60-637 Poznań, Poland;
| | - Adam Cieślak
- Department of Animal Nutrition and Feed Management, Poznań University of Life Sciences, Wołyńska 33, 60-637 Poznań, Poland;
| | - Kamil Gruszczyński
- Sub-Department of Pathophysiology, Department of Preclinical of Veterinary Sciences, Faculty of Veterinary Medicine, University of Life Sciences in Lublin, Akademicka 12, 20-033 Lublin, Poland; (M.W.); (B.S.); (K.G.)
| | - Agnieszka Marek
- Department of Preventive Veterinary and Avian Diseases, Faculty of Veterinary Medicine, University of Life Sciences in Lublin, 20-950 Lublin, Poland;
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Ma YN, Jiang X, Liu H, Song P, Tang W. Conversion therapy for initially unresectable hepatocellular carcinoma: Current status and prospects. Biosci Trends 2024; 17:415-426. [PMID: 38143080 DOI: 10.5582/bst.2023.01322] [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: 12/26/2023]
Abstract
Research has shown that locoregional and/or systemic treatments can reduce the tumor stage, enabling radical surgical resection in patients with initially unresectable hepatocellular carcinoma. This is referred to as conversion therapy. Patients who undergo conversion therapy followed by curative surgery experience a significant survival benefit compared to those who receive chemotherapy alone, those who are successfully downstaged with conversion therapy but not treated with surgery, or those who are treated with upfront surgery. Several treatments have been studied as conversion therapy. However, the success rate of conversion varies greatly, ranging from 0.8% to 60%. Combined locoregional plus systemic conversion therapy has demonstrated significant clinical advantages, with a conversion rate of up to 60%, an objective remission rate of 96% for patients, and a disease control rate of up to 100%. However, patients who underwent conversion therapy experienced significantly more complications than those who underwent direct LR without conversion therapy. Conversion therapy can cause hepatotoxicity, bone marrow suppression, local adhesions, increased fragility of blood vessels and liver tissues, and hepatic edema, which can increase the difficulty of surgery. In addition, criteria need to be established to evaluate the efficacy of conversion therapy and subsequent treatment. Further clinical evidence in this area is urgently needed.
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Affiliation(s)
- Ya-Nan Ma
- Department of Gastroenterology, Hainan General Hospital, Hainan Affiliated Hospital of Hainan Medical University, Haikou, China
- Center for Clinical Sciences, National Center for Global Health and Medicine, Tokyo, Japan
| | - Xuemei Jiang
- Department of Gastroenterology, Hainan General Hospital, Hainan Affiliated Hospital of Hainan Medical University, Haikou, China
| | - Hui Liu
- Department of Interventional Radiology, Haikou Affiliated Hospital of Central South University Xiangya School of Medicine, Haikou, China
| | - Peipei Song
- Center for Clinical Sciences, National Center for Global Health and Medicine, Tokyo, Japan
| | - Wei Tang
- International Health Care Center, National Center for Global Health and Medicine, Tokyo, Japan
- Haikou Affiliated Hospital of Central South University Xiangya School of Medicine, Haikou, China
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9
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Li B, Bo S, Sheng Z, Zhu H, Jiang Y, Yang B. Hepatoprotective Activity and Mechanisms of Prenylated Stilbenoids. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2024; 72:1618-1629. [PMID: 38189644 DOI: 10.1021/acs.jafc.3c09515] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/09/2024]
Abstract
Dietary prenylated stilbenoids, found in various food sources, offer multiple health benefits, including liver protection. However, the underlying mechanisms of hepatoprotection remain unclear. In this study, we synthesized 13 natural prenylated stilbenoids and examined their hepatoprotective activities, with silent mating type information regulation 2 homologue-1 (SIRT1) as the primary target for screening. Among all of the prenylated stilbenoids tested, 4-C-geranyl oxyresveratrol demonstrated superior performance. It activated SIRT1 activity more effectively than resveratrol, a well-known SIRT1 activator. To further investigate the mechanism of liver protection, two in vitro models were used: the palmitic acid-induced lipid accumulation model and the H2O2-induced apoptosis model. Our findings suggested that 4-C-geranyl oxyresveratrol mitigated lipid accumulation through the SIRT1-PGC1α pathway, reduced apoptosis via the SIRT1-p53-p21 pathway, and exerted antioxidant effects through the SIRT1-Nrf2 pathway. These findings provide new insights into the chemical basis of the health benefits of prenylated stilbenoids and their potential use as functional food additives.
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Affiliation(s)
- Bailin Li
- Key State Laboratory of Plant Diversity and Specialty Crops, Guangdong Provincial Key Laboratory of Applied Botany, Key Laboratory of South China Agricultural Plant Molecular Analysis and Genetic Improvement, South China Botanical Garden, Chinese Academy of Sciences, Guangzhou 510650, China
- South China National Botanical Garden, Guangzhou 510650, China
- University of Chinese Academy of Sciences, Beijing 100049, China
| | - Shengtao Bo
- Zhaoqing Public Security Judicial Appraisal Center, Zhaoqing 526000, China
| | - Zhili Sheng
- Key State Laboratory of Plant Diversity and Specialty Crops, Guangdong Provincial Key Laboratory of Applied Botany, Key Laboratory of South China Agricultural Plant Molecular Analysis and Genetic Improvement, South China Botanical Garden, Chinese Academy of Sciences, Guangzhou 510650, China
- South China National Botanical Garden, Guangzhou 510650, China
- University of Chinese Academy of Sciences, Beijing 100049, China
| | - Hong Zhu
- Key State Laboratory of Plant Diversity and Specialty Crops, Guangdong Provincial Key Laboratory of Applied Botany, Key Laboratory of South China Agricultural Plant Molecular Analysis and Genetic Improvement, South China Botanical Garden, Chinese Academy of Sciences, Guangzhou 510650, China
- South China National Botanical Garden, Guangzhou 510650, China
- University of Chinese Academy of Sciences, Beijing 100049, China
| | - Yueming Jiang
- Key State Laboratory of Plant Diversity and Specialty Crops, Guangdong Provincial Key Laboratory of Applied Botany, Key Laboratory of South China Agricultural Plant Molecular Analysis and Genetic Improvement, South China Botanical Garden, Chinese Academy of Sciences, Guangzhou 510650, China
- South China National Botanical Garden, Guangzhou 510650, China
- University of Chinese Academy of Sciences, Beijing 100049, China
| | - Bao Yang
- Key State Laboratory of Plant Diversity and Specialty Crops, Guangdong Provincial Key Laboratory of Applied Botany, Key Laboratory of South China Agricultural Plant Molecular Analysis and Genetic Improvement, South China Botanical Garden, Chinese Academy of Sciences, Guangzhou 510650, China
- South China National Botanical Garden, Guangzhou 510650, China
- University of Chinese Academy of Sciences, Beijing 100049, China
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10
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Krolevets TS, Livzan MA. Metabolic-associated fatty liver disease (NAFLD) as a cancer risk factor. EXPERIMENTAL AND CLINICAL GASTROENTEROLOGY 2023:120-127. [DOI: 10.31146/1682-8658-ecg-211-3-120-127] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/17/2024]
Abstract
The purpose of this review was to update information on the prevalence and relationship of cancer development of various localizations with non-alcoholic, metabolic-associated fatty liver disease (NAFLD/MAFLD). Discussion: The second most common cause of death among patients with NAFLD are malignant neoplasms both in the gastrointestinal tract (liver, colon, esophagus, stomach and pancreas) and in other organs (kidneys, prostate gland in men and mammary gland in women). Obesity and other metabolic disorders are associated with an increase in morbidity or mortality from various types of cancer. Due to the high prevalence of NAFLD among patients with metabolic syndrome, type 2 diabetes mellitus, an extrapolation of this development is assumed among patients with NAFLD. Metabolic disorders, imbalance of the intestinal microflora are considered as possible pathogenetic mechanisms for increasing the risk of cancer among patients suffering from NAFLD. Conclusion: in addition to the risk of developing hepatocellular carcinoma as a natural course of the disease, convincing evidence is accumulating for the role of NAFLD as an independent risk factor for the development and progression of cancer, especially in the gastrointestinal tract.
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11
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Shah UA, Ballinger TJ, Bhandari R, Dieli-Conwright CM, Guertin KA, Hibler EA, Kalam F, Lohmann AE, Ippolito JE. Imaging modalities for measuring body composition in patients with cancer: opportunities and challenges. J Natl Cancer Inst Monogr 2023; 2023:56-67. [PMID: 37139984 PMCID: PMC10157788 DOI: 10.1093/jncimonographs/lgad001] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2022] [Revised: 12/15/2022] [Accepted: 12/30/2022] [Indexed: 05/05/2023] Open
Abstract
Body composition assessment (ie, the measurement of muscle and adiposity) impacts several cancer-related outcomes including treatment-related toxicities, treatment responses, complications, and prognosis. Traditional modalities for body composition measurement include body mass index, body circumference, skinfold thickness, and bioelectrical impedance analysis; advanced imaging modalities include dual energy x-ray absorptiometry, computerized tomography, magnetic resonance imaging, and positron emission tomography. Each modality has its advantages and disadvantages, thus requiring an individualized approach in identifying the most appropriate measure for specific clinical or research situations. Advancements in imaging approaches have led to an abundance of available data, however, the lack of standardized thresholds for classification of abnormal muscle mass or adiposity has been a barrier to adopting these measurements widely in research and clinical care. In this review, we discuss the different modalities in detail and provide guidance on their unique opportunities and challenges.
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Affiliation(s)
- Urvi A Shah
- Department of Medicine, Myeloma Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Department of Medicine, Weill Cornell Medical College, New York, NY, USA
| | - Tarah J Ballinger
- Department of Medicine, Indiana University Simon Comprehensive Cancer Center, Indianapolis, IN, USA
| | - Rusha Bhandari
- Department of Pediatrics, City of Hope, Duarte, CA, USA
- Department of Population Science, City of Hope, Duarte, CA, USA
| | - Christina M Dieli-Conwright
- Division of Population Sciences, Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
| | - Kristin A Guertin
- Department of Public Health Sciences, University of Connecticut Health, Farmington, CT, USA
| | - Elizabeth A Hibler
- Department of Preventive Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA
| | - Faiza Kalam
- Department of Preventive Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA
| | - Ana Elisa Lohmann
- Department of Medical Oncology, Schulich School of Medicine and Dentistry, University of Western Ontario, London, ON, Canada
| | - Joseph E Ippolito
- Department of Radiology, Washington University School of Medicine, St. Louis, MO, USA
- Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St Louis, MO, USA
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12
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Jing M, Sun J, Xi H, Liu Z, Zhang S, Deng L, Han T, Zhang B, Lin X, Zhou J. Abdominal virtual non-contrast images derived from energy spectrum CT to evaluate chemotherapy-related fatty liver disease. Quant Imaging Med Surg 2023; 13:669-681. [PMID: 36819287 PMCID: PMC9929393 DOI: 10.21037/qims-22-742] [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: 07/15/2022] [Accepted: 11/24/2022] [Indexed: 01/15/2023]
Abstract
Background Chemotherapy-related fatty liver disease (CRFLD) is an important evaluation in patients undergoing computed tomography (CT) for cancer follow-up. This study set out to explore the feasibility of using abdominal virtual non-contrast (VNC) images derived from energy spectrum CT to evaluate CRFLD and reduce the radiation dose. Methods A total of 160 eligible consecutive patients who underwent energy spectrum CT at Lanzhou University Second Hospital between June 2020 and July 2021 were retrospectively enrolled. The average CT attenuation values of the liver and spleen and the liver-to-spleen ratio (LSR) were measured by two independent blinded radiologists on true non-contrast (TNC) images and three types of VNC image. The diagnostic performance of the LSR for CRFLD, image quality, and diagnostic confidence were compared between the two types of imaging. Results The average CT attenuation values of the liver and spleen were significantly lower on VNC images than on TNC images (P<0.05), whereas the LSR showed good agreement between the two (P>0.05). The average CT attenuation values of the liver and the LSR measured on the TNC and three types of VNC image were significantly lower in patients with CRFLD than in those without CRFLD (P<0.001). The area under the curve (AUC) values of the LSR for the diagnosis of CRFLD calculated on TNC and three types of VNC image were 0.870 (95% CI: 0.808-0.918), 0.852 (95% CI: 0.787-0.903), 0.819 (95% CI: 0.750-0.875), and 0.851 (95% CI: 0.786-0.902), respectively. The DeLong test confirmed the consistency of TNC and VNC images of diagnostic efficacy (P>0.05). There were no significant differences in image quality or diagnostic confidence between the TNC and three types of VNC image (P>0.05). When VNC imaging was applied, the radiation dose was reduced by approximately 25.0%. Conclusions VNC imaging could become a reliable alternative to TNC imaging for the clinical evaluation of patients with CRFLD and could reduce the radiation dose by up to 25%.
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Affiliation(s)
- Mengyuan Jing
- Department of Radiology, Lanzhou University Second Hospital, Lanzhou, China;,Second Clinical School, Lanzhou University, Lanzhou, China;,Key Laboratory of Medical Imaging of Gansu Province, Lanzhou, China;,Gansu International Scientific and Technological Cooperation Base of Medical Imaging Artificial Intelligence, Lanzhou, China
| | - Jiachen Sun
- Department of Radiology, Lanzhou University Second Hospital, Lanzhou, China;,Second Clinical School, Lanzhou University, Lanzhou, China;,Key Laboratory of Medical Imaging of Gansu Province, Lanzhou, China;,Gansu International Scientific and Technological Cooperation Base of Medical Imaging Artificial Intelligence, Lanzhou, China
| | - Huaze Xi
- Department of Radiology, Lanzhou University Second Hospital, Lanzhou, China;,Second Clinical School, Lanzhou University, Lanzhou, China;,Key Laboratory of Medical Imaging of Gansu Province, Lanzhou, China;,Gansu International Scientific and Technological Cooperation Base of Medical Imaging Artificial Intelligence, Lanzhou, China
| | - Zhuoheng Liu
- Computed Tomography Research Center, GE Healthcare China, Beijing, China
| | - Shuai Zhang
- Computed Tomography Research Center, GE Healthcare China, Beijing, China
| | - Liangna Deng
- Department of Radiology, Lanzhou University Second Hospital, Lanzhou, China;,Second Clinical School, Lanzhou University, Lanzhou, China;,Key Laboratory of Medical Imaging of Gansu Province, Lanzhou, China;,Gansu International Scientific and Technological Cooperation Base of Medical Imaging Artificial Intelligence, Lanzhou, China
| | - Tao Han
- Department of Radiology, Lanzhou University Second Hospital, Lanzhou, China;,Second Clinical School, Lanzhou University, Lanzhou, China;,Key Laboratory of Medical Imaging of Gansu Province, Lanzhou, China;,Gansu International Scientific and Technological Cooperation Base of Medical Imaging Artificial Intelligence, Lanzhou, China
| | - Bin Zhang
- Department of Radiology, Lanzhou University Second Hospital, Lanzhou, China;,Second Clinical School, Lanzhou University, Lanzhou, China;,Key Laboratory of Medical Imaging of Gansu Province, Lanzhou, China;,Gansu International Scientific and Technological Cooperation Base of Medical Imaging Artificial Intelligence, Lanzhou, China
| | - Xiaoqiang Lin
- Department of Radiology, Lanzhou University Second Hospital, Lanzhou, China;,Second Clinical School, Lanzhou University, Lanzhou, China;,Key Laboratory of Medical Imaging of Gansu Province, Lanzhou, China;,Gansu International Scientific and Technological Cooperation Base of Medical Imaging Artificial Intelligence, Lanzhou, China
| | - Junlin Zhou
- Department of Radiology, Lanzhou University Second Hospital, Lanzhou, China;,Second Clinical School, Lanzhou University, Lanzhou, China;,Key Laboratory of Medical Imaging of Gansu Province, Lanzhou, China;,Gansu International Scientific and Technological Cooperation Base of Medical Imaging Artificial Intelligence, Lanzhou, China
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13
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Tu T, Alba MM, Datta AA, Hong H, Hua B, Jia Y, Khan J, Nguyen P, Niu X, Pammidimukkala P, Slarve I, Tang Q, Xu C, Zhou Y, Stiles BL. Hepatic macrophage mediated immune response in liver steatosis driven carcinogenesis. Front Oncol 2022; 12:958696. [PMID: 36276076 PMCID: PMC9581256 DOI: 10.3389/fonc.2022.958696] [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: 05/31/2022] [Accepted: 08/17/2022] [Indexed: 12/02/2022] Open
Abstract
Obesity confers an independent risk for carcinogenesis. Classically viewed as a genetic disease, owing to the discovery of tumor suppressors and oncogenes, genetic events alone are not sufficient to explain the progression and development of cancers. Tumor development is often associated with metabolic and immunological changes. In particular, obesity is found to significantly increase the mortality rate of liver cancer. As its role is not defined, a fundamental question is whether and how metabolic changes drive the development of cancer. In this review, we will dissect the current literature demonstrating that liver lipid dysfunction is a critical component driving the progression of cancer. We will discuss the involvement of inflammation in lipid dysfunction driven liver cancer development with a focus on the involvement of liver macrophages. We will first discuss the association of steatosis with liver cancer. This will be followed with a literature summary demonstrating the importance of inflammation and particularly macrophages in the progression of liver steatosis and highlighting the evidence that macrophages and macrophage produced inflammatory mediators are critical for liver cancer development. We will then discuss the specific inflammatory mediators and their roles in steatosis driven liver cancer development. Finally, we will summarize the molecular pattern (PAMP and DAMP) as well as lipid particle signals that are involved in the activation, infiltration and reprogramming of liver macrophages. We will also discuss some of the therapies that may interfere with lipid metabolism and also affect liver cancer development.
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Affiliation(s)
- Taojian Tu
- Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA, United States
| | - Mario M. Alba
- Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA, United States
| | - Aditi A. Datta
- Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA, United States
| | - Handan Hong
- Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA, United States
| | - Brittney Hua
- Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA, United States
| | - Yunyi Jia
- Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA, United States
| | - Jared Khan
- Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA, United States
| | - Phillip Nguyen
- Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA, United States
| | - Xiatoeng Niu
- Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA, United States
| | - Pranav Pammidimukkala
- Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA, United States
| | - Ielyzaveta Slarve
- Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA, United States
| | - Qi Tang
- Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA, United States
| | - Chenxi Xu
- Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA, United States
| | - Yiren Zhou
- Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA, United States
| | - Bangyan L. Stiles
- Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA, United States
- Department of Pathology, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
- *Correspondence: Bangyan L. Stiles,
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14
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Sakai N, Hayano K, Mishima T, Furukawa K, Takayashiki T, Kuboki S, Takano S, Kawasaki Y, Matsubara H, Ohtsuka M. Fat signal fraction assessed with MRI predicts hepatic recurrence following hepatic resection for colorectal liver metastases. Langenbecks Arch Surg 2022; 407:1981-1989. [PMID: 35362752 DOI: 10.1007/s00423-022-02482-z] [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: 10/04/2021] [Accepted: 02/20/2022] [Indexed: 12/24/2022]
Abstract
PURPOSE The effect of hepatic steatosis on the development of colorectal liver metastases (CRLM) remains unknown. This study evaluated the usefulness of fat signal fraction assessed with magnetic resonance imaging (MRI) and the effect of hepatic steatosis on hepatic recurrences following initial hepatectomy for CRLM. METHODS Between January 2013 and December 2019, 64 patients underwent initial hepatectomy for CRLM. The medical records of these patients were reviewed to evaluate the recurrence and survival outcomes. RESULTS The fat signal fraction was positively correlated with the nonalcoholic fatty liver disease activity score and liver-spleen ratio. Recurrence following the initial hepatectomy was observed in 48/64 patients, and hepatic recurrence was observed in 30/64 patients. The fat signal fraction was significantly higher in patients with hepatic recurrence after initial hepatectomy. The hepatic recurrence rate was 69.2% in patients with fat signal fraction ≥ 0.0258, which was significantly higher than that in patients with fat signal fraction < 0.0258. Hepatic recurrence-free survival rate was significantly higher in patients with fat signal fraction < 0.0258 than in those with fat signal fraction ≥ 0.0258. Multivariate analyses revealed that fat signal fraction ≥ 0.0258 was an independent risk factor for hepatic recurrence. CONCLUSION The fat signal fraction assessed with MRI was significantly associated with hepatic recurrence following initial hepatectomy for CRLM.
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Affiliation(s)
- Nozomu Sakai
- Department of General Surgery, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba, 260-8670, Japan
| | - Koichi Hayano
- Department of Frontier Surgery, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Takashi Mishima
- Department of General Surgery, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba, 260-8670, Japan
| | - Katsunori Furukawa
- Department of General Surgery, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba, 260-8670, Japan
| | - Tsukasa Takayashiki
- Department of General Surgery, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba, 260-8670, Japan
| | - Satoshi Kuboki
- Department of General Surgery, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba, 260-8670, Japan
| | - Shigetsugu Takano
- Department of General Surgery, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba, 260-8670, Japan
| | - Yohei Kawasaki
- Faculty of Nursing, Japanese Red Cross College of Nursing, Tokyo, Japan
| | - Hisahiro Matsubara
- Department of Frontier Surgery, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Masayuki Ohtsuka
- Department of General Surgery, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba, 260-8670, Japan.
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15
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Liu ZP, Chen WY, Zhang YQ, Jiang Y, Bai J, Pan Y, Zhong SY, Zhong YP, Chen ZY, Dai HS. Postoperative morbidity adversely impacts oncological prognosis after curative resection for hilar cholangiocarcinoma. World J Gastroenterol 2022; 28:948-960. [PMID: 35317056 PMCID: PMC8908289 DOI: 10.3748/wjg.v28.i9.948] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/01/2021] [Revised: 11/25/2021] [Accepted: 01/29/2022] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Postoperative morbidity after curative resection for hilar cholangiocarcinoma (HCCA) is common; however, whether it has an impact on oncological prognosis is unknown.
AIM To evaluate the influence of postoperative morbidity on tumor recurrence and mortality after curative resection for HCCA.
METHODS Patients with recently diagnosed HCCA who had undergone curative resection between January 2010 and December 2017 at The First Affiliated Hospital of Army Medical University in China were enrolled. The independent risk factors for morbidity in the 30 d after surgery were investigated, and links between postoperative morbidity and patient characteristics and outcomes were assessed. Postoperative morbidities were divided into five grades based on the Clavien-Dindo classification, and major morbidities were defined as Clavien-Dindo ≥ 3. Univariate and multivariate Cox regression analyses were used to evaluate the risk factors for recurrence-free survival (RFS) and overall survival (OS).
RESULTS Postoperative morbidity occurred in 146 out of 239 patients (61.1%). Multivariate logistic regression revealed that cirrhosis, intraoperative blood loss > 500 mL, diabetes mellitus, and obesity were independent risk factors. Postoperative morbidity was associated with decreased OS and RFS (OS: 18.0 mo vs 31.0 mo, respectively, P = 0.003; RFS: 16.0 mo vs 26.0 mo, respectively, P = 0.002). Multivariate Cox regression analysis indicated that postoperative morbidity was independently associated with decreased OS [hazard ratios (HR): 1.557, 95% confidence interval (CI): 1.119-2.167, P = 0.009] and RFS (HR: 1.535, 95%CI: 1.117-2.108, P = 0.008). Moreover, major morbidity was independently associated with decreased OS (HR: 2.175; 95%CI: 1.470-3.216, P < 0.001) and RFS (HR: 2.054; 95%CI: 1.400-3.014, P < 0.001) after curative resection for HCCA.
CONCLUSION Postoperative morbidity (especially major morbidity) may be an independent risk factor for unfavorable prognosis in HCCA patients following curative resection.
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Affiliation(s)
- Zhi-Peng Liu
- Department of Hepatobiliary Surgery, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing 400038, China
| | - Wei-Yue Chen
- Department of Clinical Center of Oncology, Lishui Hospital of Zhejiang University, Lishui 323000, Zhejiang Province, China
| | - Yan-Qi Zhang
- Department of Health Statistics, Third Military Medical University (Army Medical University), Chongqing 400038, China
| | - Yan Jiang
- Department of Hepatobiliary Surgery, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing 400038, China
| | - Jie Bai
- Department of Hepatobiliary Surgery, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing 400038, China
| | - Yu Pan
- Department of Hepatobiliary Surgery, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing 400038, China
| | - Shi-Yun Zhong
- Department of Hepatobiliary Surgery, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing 400038, China
| | - Yun-Ping Zhong
- Department of Hepatobiliary Surgery, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing 400038, China
| | - Zhi-Yu Chen
- Department of Hepatobiliary Surgery, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing 400038, China
| | - Hai-Su Dai
- Department of Hepatobiliary Surgery, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing 400038, China
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