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Mann EM, Akambase J, Searle K, Hunt S, Debes JD. Differential Association of Hepatocellular Carcinoma Related to Hepatitis B Between Urban and Rural Areas in Africa Using Satellite Spatial Scaling Data. JCO Glob Oncol 2025; 11:e2400543. [PMID: 40184566 PMCID: PMC12004990 DOI: 10.1200/go-24-00543] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2024] [Revised: 01/27/2025] [Accepted: 02/18/2025] [Indexed: 04/06/2025] Open
Abstract
PURPOSE Sub-Saharan Africa carries one of the highest burdens of hepatocellular carcinoma (HCC) in the world, with hepatitis B virus (HBV) as the most common cause. Studies in several regions of the world suggest important cancer differences in rural versus urban settings, but limited studies have been performed in Africa. METHODS We performed a scoping review and pooled analysis of studies on HCC in Africa. Using land use data from the European Space Agency, we calculated the distance in kilometers from each study site to the nearest rural area. Regression models were fit to estimate the association between distance to the nearest rural area and HBV, sex, and weighted mean age. RESULTS Data from 57 studies including 10,907 patients across 36 towns/cities were included in our analysis. Proximity to rural areas was associated with a higher frequency of HBV-associated HCC in assessment of distance both at midpoint and at quartiles after controlling for country: risk ratio (RR) 1.71 (95% CI, 1.52 to 1.93) and RR 1.51 (95% CI, 1.25 to 1.84), respectively. No association was found between sex and proximity to a rural area: RR 1.02 (95% CI, 0.96 to 1.08). The weighted mean age across the four distance quartiles was 50.09, 53.43, 47.98, and 53.35 years with no statistically significant difference found across the quartiles (P = .81). CONCLUSION Individuals living in rural Africa have a higher rate of HBV-related HCC compared with other liver diseases. Increased HBV awareness efforts in these areas should be considered.
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Affiliation(s)
- Erin M. Mann
- Division of Epidemiology and Community Health, School of Public Health, University of Minnesota, Minneapolis, MN
| | | | - Kelly Searle
- Division of Epidemiology and Community Health, School of Public Health, University of Minnesota, Minneapolis, MN
| | - Shanda Hunt
- University Libraries, University of Minnesota, Minneapolis, MN
| | - Jose D. Debes
- Department of Medicine, University of Minnesota, Minneapolis, MN
- Department of Medicine, Arusha Lutheran Medical Center, Arusha, Tanzania
- Department of Gastroenterology, Erasmus MC, the Netherlands
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Maponga TG, McNaughton AL, Campbell C, de Cesare M, Mokaya J, Lumley SF, Bonsall D, Ip CL, Chai H, Van Rensburg C, Glashoff RH, Waddilove E, Preiser W, Blackard JT, Ansari MA, Kramvis A, Andersson MI, Matthews PC. A putative hepatitis B virus sequence motif associated with hepatocellular carcinoma in South African adults. Ann Hepatol 2025; 30:101763. [PMID: 39986372 DOI: 10.1016/j.aohep.2024.101763] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/07/2024] [Revised: 09/27/2024] [Accepted: 11/14/2024] [Indexed: 02/24/2025]
Abstract
INTRODUCTION AND OBJECTIVES Chronic hepatitis B virus (HBV) infection is a major risk factor for hepatocellular carcinoma (HCC). In African populations, HCC frequently presents at an advanced stage with poor outcomes. We applied whole genome sequencing (WGS) to compare HBV genomes in individuals with and without HCC. MATERIALS AND METHODS We identified adults with HBV infection, with and without complicating HCC, in Cape Town, South Africa. We generated HBV WGS using pan-genotypic probe-based enrichment followed by Illumina sequencing. RESULTS Compared to the non-HCC group, HCC patients were more likely to be male (p < 0.0001), older (p = 0.01), HIV-negative (p = 0.006), and have higher HBV viral loads (p < 0.0001). Among 19 HCC and 12 non-HCC patients for whom WGS was obtained, genotype A dominated (74 %), of which 96 % were subgenotype A1. PreS2 deletions (Δ38-55) were enriched in HBV sequences from HCC patients (n = 7). The sequence motif most strongly associated with HCC comprised either a deletion or polymorphism at site T53 in PreS2 - collectively coined 'non-T53' - together with a basal core promoter (BCP) mutation G1764A (AUROC = 0.79). CONCLUSIONS In this setting, HBV sequence polymorphisms and deletions are associated with HCC, and 'non-T53 + G1764A' represents a putative signature motif for HCC. Additional investigations are needed to disaggregate the impact of other demographic, clinical, and environmental influences, to ascertain the extent to which viral polymorphisms contribute to oncogenesis, and to determine whether HBV sequence is a useful biomarker for HCC risk stratification.
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Affiliation(s)
- Tongai G Maponga
- Division of Medical Virology, Stellenbosch University, Faculty of Medicine and Health Sciences, Tygerberg, Cape Town, South Africa; National Health Laboratory Service, Tygerberg Business Unit, Tygerberg, Cape Town, South Africa
| | | | - Cori Campbell
- Nuffield Department of Medicine, University of Oxford, Oxford, UK
| | | | - Jolynne Mokaya
- Parasites and Microbes, Wellcome Sanger Institute, Hinxton, UK
| | - Sheila F Lumley
- Nuffield Department of Medicine, University of Oxford, Oxford, UK; Department of Infectious Diseases and Microbiology, Oxford University Hospitals NHS Foundation Trust, John Radcliffe Hospital, Headley Way, Oxford OX3 9DU, UK
| | - David Bonsall
- Nuffield Department of Medicine, University of Oxford, Oxford, UK; Department of Infectious Diseases and Microbiology, Oxford University Hospitals NHS Foundation Trust, John Radcliffe Hospital, Headley Way, Oxford OX3 9DU, UK; Big Data Institute, Old Road, Oxford OX3 7FZ, UK
| | - Camilla Lc Ip
- Nuffield Department of Medicine, University of Oxford, Oxford, UK
| | - Haiting Chai
- Nuffield Department of Medicine, University of Oxford, Oxford, UK
| | - Christo Van Rensburg
- Division of Gastroenterology, Stellenbosch University, Faculty of Medicine and Health Sciences, Tygerberg, Cape Town, South Africa
| | - Richard H Glashoff
- National Health Laboratory Service, Tygerberg Business Unit, Tygerberg, Cape Town, South Africa; Immunology Unit, Division of Medical Microbiology, Stellenbosch University, Faculty of Medicine and Health Sciences, Tygerberg, Cape Town, South Africa
| | | | - Wolfgang Preiser
- Division of Medical Virology, Stellenbosch University, Faculty of Medicine and Health Sciences, Tygerberg, Cape Town, South Africa; National Health Laboratory Service, Tygerberg Business Unit, Tygerberg, Cape Town, South Africa
| | - Jason T Blackard
- University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | - M Azim Ansari
- Nuffield Department of Medicine, University of Oxford, Oxford, UK
| | - Anna Kramvis
- Hepatitis Virus Diversity Research Unit, Department of Internal Medicine, University of the Witwatersrand, 7 York Road, Parktown, 2193 Johannesburg, South Africa
| | - Monique I Andersson
- Division of Medical Virology, Stellenbosch University, Faculty of Medicine and Health Sciences, Tygerberg, Cape Town, South Africa; Nuffield Department of Medicine, University of Oxford, Oxford, UK; Department of Infectious Diseases and Microbiology, Oxford University Hospitals NHS Foundation Trust, John Radcliffe Hospital, Headley Way, Oxford OX3 9DU, UK
| | - Philippa C Matthews
- The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK; Division of Infection and Immunity, University College London, Gower Street, London WC1E 6BT, UK; Department of Infectious Diseases, University College London Hospital, Euston Road, London NW1 2BU, UK.
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3
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Xu B, Luo Z, Niu X, Li Z, Lu Y, Li J. Fungi, immunosenescence and cancer. Semin Cancer Biol 2025; 109:67-82. [PMID: 39788169 DOI: 10.1016/j.semcancer.2025.01.002] [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: 11/05/2024] [Revised: 12/22/2024] [Accepted: 01/03/2025] [Indexed: 01/12/2025]
Abstract
Fungal microbes are a small but immunoreactive component of the human microbiome, which may influence cancer development, progression and therapeutic response. Immunosenescence is a process of immune dysfunction that occurs with aging, including lymphoid organ remodeling, contributing to alterations in the immune system in the elderly, which plays a critical role in many aspects of cancer. There is evidence for the interactions between fungi and immunosenescence in potentially regulating cancer progression and remodeling the tumor microenvironment (TME). In this review, we summarize potential roles of commensal and pathogenic fungi in modulating cancer-associated processes and provide more-detailed discussions on the mechanisms of which fungi affect tumor biology, including local and distant regulation of the TME, modulating antitumor immune responses and interactions with neighboring bacterial commensals. We also delineate the features of immunosenescence and its influence on cancer development and treatment, and highlight the interactions between fungi and immunosenescence in cancer. We discuss the prospects and challenges for harnessing fungi and immunosenescence in cancer diagnosis and/or treatment. Considering the limited understanding and techniques in conducting such research, we also provide our view on how to overcome challenges faced by the exploration of fungi, immunosenescence and their interactions on tumor biology.
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Affiliation(s)
- Bin Xu
- Jiangxi Health Committee Key (JHCK) Laboratory of Tumor Metastasis, Jiangxi Key Laboratory of Oncology, Jiangxi Cancer Hospital (The Second Affiliated Hospital of Nanchang Medical College), Nanchang, Jiangxi 330029, China
| | - Zan Luo
- Jiangxi Health Committee Key (JHCK) Laboratory of Tumor Metastasis, Jiangxi Key Laboratory of Oncology, Jiangxi Cancer Hospital (The Second Affiliated Hospital of Nanchang Medical College), Nanchang, Jiangxi 330029, China
| | - Xing Niu
- Experimental Center of BIOQGene, YuanDong International Academy of Life Sciences, 999077, China; Voylin Institute for Translation Medicine, Xiamen, Fujian 361000, China
| | - Zhi Li
- Jiangxi Health Committee Key (JHCK) Laboratory of Tumor Metastasis, Jiangxi Key Laboratory of Oncology, Jiangxi Cancer Hospital (The Second Affiliated Hospital of Nanchang Medical College), Gannan Medical University, Ganzhou, Jiangxi 341000, China
| | - Yeping Lu
- Department of Neurosurgery, The Fifth Hospital of Wuhan, Wuhan, Hubei 430050, China.
| | - Junyu Li
- Department of Radiation Oncology, Jiangxi Key Laboratory of Oncology, Jiangxi Cancer Hospital (The Second Affiliated Hospital of Nanchang Medical College), Nanchang, Jiangxi 330029, China; The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, Zhejiang 310022, China.
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Hwang SY, Danpanichkul P, Agopian V, Mehta N, Parikh ND, Abou-Alfa GK, Singal AG, Yang JD. Hepatocellular carcinoma: updates on epidemiology, surveillance, diagnosis and treatment. Clin Mol Hepatol 2025; 31:S228-S254. [PMID: 39722614 PMCID: PMC11925437 DOI: 10.3350/cmh.2024.0824] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/22/2024] [Revised: 11/08/2024] [Accepted: 12/20/2024] [Indexed: 12/28/2024] Open
Abstract
Hepatocellular carcinoma (HCC) is a major global burden, ranking as the third leading cause of cancer-related mortality. HCC due to chronic hepatitis B virus (HBV) or C virus (HCV) infection has decreased due to universal vaccination for HBV and effective antiviral therapy for both HBV and HCV, but HCC related to metabolic dysfunction-associated steatotic liver disease and alcohol-associated liver disease is increasing. Biannual liver ultrasonography and serum α-fetoprotein are the primary surveillance tools for early HCC detection among high-risk patients (e.g., cirrhosis, chronic HBV). Alternative surveillance tools such as blood-based biomarker panels and abbreviated magnetic resonance imaging (MRI) are being investigated. Multiphasic computed tomography or MRI is the standard for HCC diagnosis, but histological confirmation should be considered, especially when inconclusive findings are seen on cross-sectional imaging. Staging and treatment decisions are complex and should be made in multidisciplinary settings, incorporating multiple factors including tumor burden, degree of liver dysfunction, patient performance status, available expertise, and patient preferences. Early-stage HCC is best treated with curative options such as resection, ablation, or transplantation. For intermediate-stage disease, locoregional therapies are primarily recommended although systemic therapies may be preferred for patients with large intrahepatic tumor burden. In advanced-stage disease, immune checkpoint inhibitor-based therapy is the preferred treatment regimen. In this review article, we discuss the recent global epidemiology, risk factors, and HCC care continuum encompassing surveillance, diagnosis, staging, and treatments.
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Affiliation(s)
- Soo Young Hwang
- Department of Internal Medicine, University of Maryland Medical Center, Midtown Campus, Baltimore, Maryland, USA
| | - Pojsakorn Danpanichkul
- Department of Internal Medicine, Texas Tech University Health Sciences Center, Lubbock, Texas, USA
| | - Vatche Agopian
- Dumont-UCLA Transplant and Liver Cancer Centers, Department of Surgery, David Geffen School of Medicine at UCLA, Los Angeles, California, USA
| | - Neil Mehta
- Division of Gastroenterology, Department of Medicine, University of California, San Francisco, California, USA
| | - Neehar D. Parikh
- Division of Gastroenterology and Hepatology, University of Michigan, Ann Arbor, Michigan, USA
| | - Ghassan K. Abou-Alfa
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, USA
- Department of Medicine, Weill Medical College at Cornell University, New York, USA
- Trinity College Dublin, Dublin, Ireland
| | - Amit G. Singal
- Division of Digestive and Liver Diseases, UT Southwestern Medical Center, Dallas, Texas, USA
| | - Ju Dong Yang
- Karsh Division of Gastroenterology and Hepatology, Comprehensive Transplant Center, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA
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Cao HH, Molina S, Sumner S, Rushing BR. An untargeted metabolomic analysis of acute AFB1 treatment in liver, breast, and lung cells. PLoS One 2025; 20:e0313159. [PMID: 39883710 PMCID: PMC11781672 DOI: 10.1371/journal.pone.0313159] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2024] [Accepted: 10/18/2024] [Indexed: 02/01/2025] Open
Abstract
Aflatoxin B1 (AFB1) is a class 1 carcinogen and mycotoxin known to contribute to the development of hepatocellular carcinoma (HCC), growth impairment, altered immune system modulation, and malnutrition. AFB1 is synthesized by Aspergillus flavus and is known to widely contaminate foodstuffs, particularly maize, wheat, and groundnuts. The mechanism in which AFB1 causes genetic mutations has been well studied, however its metabolomic effects remained largely unknown. A better understanding of how AFB1 disrupts metabolism would provide insight into how this mycotoxin leads to carcinogenesis, growth impairment, and/or immunomodulation, and may reveal potential targets for pharmacological or nutritional interventions to protect against these effects. The current study evaluated the metabolomic effects of various doses (2.5 μM, 5 μM, 10uM) of AFB1 treatment to HepG2 (liver), MDA-MB-231 (breast), and A549 (lung) cells. Treated and control cells' metabolomic profiles were evaluated via ultra-high performance liquid chromatography-high resolution mass spectrometry (UHPLC-HRMS). Univariate and multivariate analyses revealed significant alterations in metabolite concentrations from each dose of AFB1 treatment in each cell type. Pathway analysis was then used to understand broader biochemical functions affected by AFB1 treatment in each cell type. HepG2 cell pathway analyses revealed significant pathway perturbations in lipid metabolism, carnitine synthesis, catecholamine biosynthesis, purine metabolism, and spermidine and spermine biosynthesis. Analysis of A549 cells found a greater emphasis of perturbations on various amino acids along with lipid synthesis-related pathways, and catecholamine biosynthesis. Finally, analysis of treated MDA-MB-231 cells found spermidine and spermine biosynthesis, carnitine synthesis, plasma membrane-related pathways (phosphatidylcholine synthesis and alpha linolenic acid and linoleic acid metabolism), and various amino acid metabolism pathways to be most affected. These highlighted pathways should be targeted in future investigations to evaluate their potential in mitigating or preventing the development of negative health effects associated with AFB1 exposure.
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Affiliation(s)
- Heidi H. Cao
- Department of Nutrition, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States of America
| | - Sabrina Molina
- Nutrition Research Institute, University of North Carolina Chapel Hill, Kannapolis, NC, United States of America
| | - Susan Sumner
- Department of Nutrition, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States of America
- Nutrition Research Institute, University of North Carolina Chapel Hill, Kannapolis, NC, United States of America
| | - Blake R. Rushing
- Department of Nutrition, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States of America
- Nutrition Research Institute, University of North Carolina Chapel Hill, Kannapolis, NC, United States of America
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Hussain MK, Khatoon S, Khan MF, Akhtar MS, Ahamad S, Saquib M. Coumarins as versatile therapeutic phytomolecules: A systematic review. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2024; 134:155972. [PMID: 39265442 DOI: 10.1016/j.phymed.2024.155972] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/28/2024] [Revised: 06/23/2024] [Accepted: 07/11/2024] [Indexed: 09/14/2024]
Abstract
BACKGROUND Coumarins, abundantly distributed in a plethora of biologically active compounds, serve as a fundamental motif in numerous natural products, drugs, and therapeutic leads. Despite their small size, they exhibit a diverse range of biological activities, intriguing researchers with their immense pharmacological potential. PURPOSE This study consolidates the evidence regarding the essential role of coumarins in modern drug discovery, exploring their broad-spectrum pharmaceutical effects, structural versatility, and mechanisms of action across various domains. METHODS For literature search, we utilized PubMed, Google scholar, and SciFinder databases. Keyword and keyword combinations such as "coumarins", "natural coumarins", "specific natural coumarins for particular diseases", and "therapeutic effects" were employed to retrieve relevant studies. The search encompassed articles published between 2005 and 2023. Selection criteria included studies reporting on the pharmacological activities of natural coumarins against various diseases. RESULTS The results highlight the therapeutic potential of natural coumarins against various diseases, demonstrating anti-cancer, anti-oxidant, and anti-inflammatory activities. They also act as monoamine oxidase inhibitors and phosphodiesterase inhibitors, and as anti-thrombotic, anti-diabetic, and hepatoprotective agents. They also show efficacy against diabetic nephropathy, neurodegenerative diseases, microbial infections and many other diseases. CONCLUSION This review underscores the significant role of natural coumarins in medicinal chemistry and drug discovery. Their diverse biological activities and structural versatility make them promising therapeutic agents. This study serves as a catalyst for further research in the field, aiming to address emerging challenges and opportunities in drug development.
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Affiliation(s)
- Mohd Kamil Hussain
- Department of Chemistry, Govt. Raza P.G. College, Rampur 244901, M.J.P Rohil Khand University, Bareilly, India.
| | | | - Mohammad Faheem Khan
- Department of Biotechnology, Era's Lucknow Medical College, Era University, Lucknow 226003, India
| | - Mohd Sayeed Akhtar
- Department of Botany, Gandhi Faiz-e-Aam College, Shahjahanpur 242001, India
| | - Shakir Ahamad
- Department of Chemistry, Aligarh Muslim University, Aligarh 202002, India.
| | - Mohammad Saquib
- Department of Chemistry, University of Allahabad, Prayagraj (Allahabad) 211002, India; Department of Chemistry, G. R. P. B. Degree College, P. R. S. University, Prayagraj (Allahabad) 211010, India.
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Awadh AA, Alharthi AA, Alghamdi BA, Alghamdi ST, Baqays MK, Binrabaa IS, Malli IA. Coinfection of Hepatitis B and C Viruses and Risk of Hepatocellular Carcinoma: Systematic Review and Meta-analysis. J Glob Infect Dis 2024; 16:127-134. [PMID: 39886088 PMCID: PMC11775402 DOI: 10.4103/jgid.jgid_211_23] [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: 12/17/2023] [Revised: 03/09/2024] [Accepted: 04/13/2024] [Indexed: 01/04/2025] Open
Abstract
Introduction Hepatitis B and C are viral infections causing chronic liver inflammation and, when left untreated, lead to cirrhosis and a risk for hepatocellular carcinoma, the most common type of primary liver cancer with high mortality. The hepatitis B virus-hepatitis C virus (HBV-HCV) coinfection leads to a faster progression to advanced liver diseases and higher hepatocellular carcinoma (HCC) risk than monoinfection. Unlike the relative risk for HCC due to either HBV or HCV, no recent analysis of the risk for HBV-HCV coinfection exists. Methods Based on PRISMA recommendations and guidelines, we developed a search strategy by combining the keywords ("hepatitis B") and ("hepatitis C") and ("hepatocellular carcinoma" or "liver cancer"). First, we performed a title and abstract screening and, later, a full-text screening. We extracted the demographic characteristics, such as gender, age, study design, sample size, country, and biomarkers of hepatitis B surface antigen (HBsAg), HBV DNA, HBeAg, anti-HCV, and HCV RNA. The data were assessed for quality, and the Review Manager software was used for the meta-analysis. Results We included 63 studies. The pooled analysis showed that the risk of HCC was significantly higher in the case-cohort who were positive for HBsAg (odds ratio [OR] = 9.70 [3.75, 25.12], P = 0.0001), HBV DNA or HBeAg (OR = 22.77 [10.00, 51.88], P = 0.0001), HBV and HCV coinfection (OR = 46.07 [26.33, 80.60], P = 0.0001) than the control cohort. Conclusion Chronic HBV and HCV infections are major risk factors for HCC, and their coinfection was significantly associated with an increased risk of HCC than monoinfection.
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Affiliation(s)
- Abdullah A. Awadh
- Department of Basic Medical Sciences, College of Medicine, King Saud Bin Abdulaziz University for Health Sciences, Jeddah, Saudi Arabia
- King Abdullah International Medical Research Center, Jeddah, Saudi Arabia
| | - Abdulrahman A. Alharthi
- Department of Basic Medical Sciences, College of Medicine, King Saud Bin Abdulaziz University for Health Sciences, Jeddah, Saudi Arabia
| | - Basil A. Alghamdi
- Department of Basic Medical Sciences, College of Medicine, King Saud Bin Abdulaziz University for Health Sciences, Jeddah, Saudi Arabia
| | - Seraj T. Alghamdi
- Department of Basic Medical Sciences, College of Medicine, King Saud Bin Abdulaziz University for Health Sciences, Jeddah, Saudi Arabia
| | - Mohammed K. Baqays
- Department of Basic Medical Sciences, College of Medicine, King Saud Bin Abdulaziz University for Health Sciences, Jeddah, Saudi Arabia
| | - Ibrahim S. Binrabaa
- Department of Basic Medical Sciences, College of Medicine, King Saud Bin Abdulaziz University for Health Sciences, Jeddah, Saudi Arabia
| | - Israa A. Malli
- Department of Basic Medical Sciences, College of Medicine, King Saud Bin Abdulaziz University for Health Sciences, Jeddah, Saudi Arabia
- King Abdullah International Medical Research Center, Jeddah, Saudi Arabia
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Abdelnour SA, Mahasneh ZMH, Barakat RA, Alkahtani AM, Madkour M. Microalgae: A promising strategy for aflatoxin control in poultry feeds. Toxicon 2024; 244:107770. [PMID: 38768829 DOI: 10.1016/j.toxicon.2024.107770] [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: 03/14/2024] [Revised: 05/13/2024] [Accepted: 05/17/2024] [Indexed: 05/22/2024]
Abstract
Aflatoxins are toxic compounds produced by certain molds, primarily Aspergillus species, which can contaminate crops such as grains and nuts. These toxins pose a significant health risk to animals and humans. Aflatoxin B1 (AFB1) is the most potent of these compounds and has been well-characterized to lead to diminished growth and feed efficiency by disrupting nutrient absorption and metabolism in poultry. AFB1 can trigger apoptosis and inflammation, leading to a decline in immune function and changes in blood biochemistry in poultry. Recently, there has been growing interest in using microalgae as a natural antioxidant to mitigate the effects of aflatoxins in poultry diets. Microalgae have strong antioxidant, antimicrobial, anti-apoptotic, and anti-inflammatory properties, and adding them to aflatoxin-contaminated poultry diets has been shown to improve growth and overall health. This review investigates the potential of microalgae, such as Spirulina platensis, Chlorella vulgaris, and Enteromorpha prolifera, to mitigate AFB1 contamination in poultry feeds. These microalgae contain substantial amounts of bioactive compounds, including polysaccharides, peptides, vitamins, and pigments, which possess antioxidant, antimicrobial, and detoxifying properties. Microalgae can bind to aflatoxins and prevent their absorption in the gastrointestinal tract of poultry. They can also enhance the immune system of poultry, making them more resilient to the toxic effects of AFB1. Based on the data collected, microalgae have shown promising results in combating AFB1 contamination in poultry feeds. They can bind to aflatoxins, boost the immune system, and improve feed quality. This review emphasizes the harmful effects of AFB1 on poultry and the promising role of microalgae in reducing these effects.
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Affiliation(s)
- Sameh A Abdelnour
- Department of Animal Production, Faculty of Agriculture, Zagazig University, Zagazig, 44511, Egypt.
| | - Zeinab M H Mahasneh
- Department of Animal Production, School of Agriculture, The University of Jordan, Amman, 11942, Jordan
| | - Rasha A Barakat
- Department of Physiology, Faculty of Veterinary Medicine, Damanhour University, Damanhour, 22511, Egypt
| | - Abdullah M Alkahtani
- Department of Microbiology & Clinical Parasitology College of Medicine, King Khalid University, Abha, 61413, Saudi Arabia
| | - Mahmoud Madkour
- Animal Production Department, National Research Centre, Dokki, 12622, Giza, Egypt
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Feng F, Zhao Y. Hepatocellular Carcinoma: Prevention, Diagnosis, and Treatment. Med Princ Pract 2024; 33:414-423. [PMID: 38772352 PMCID: PMC11460940 DOI: 10.1159/000539349] [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: 11/05/2023] [Accepted: 05/14/2024] [Indexed: 05/23/2024] Open
Abstract
Hepatocellular carcinoma (HCC), the most prevalent form of liver cancer globally, poses a substantial health burden. Influenced by risk factors such as hepatitis B or C virus infections, chronic consumption of alcohol, and metabolic dysfunction, its exact etiology likely involves a complex interplay between viral infection, hepatocyte mutations, and chronic liver diseases like cirrhosis and metabolic dysfunction-associated steatohepatitis, and demographic variables like sex, race, and age. Disease stage significantly impacts the prognosis of HCC. There is significant potential for life-saving and socioeconomic benefits through the implementation of surveillance programs and the introduction of low-cost screening measures for high-risk groups; these screening measures include ultrasound imaging and blood tests. Treatment options for HCC encompass liver resection, transplantation, transarterial chemoembolization, radiation therapy, chemotherapy, targeted therapy, and immunotherapy. Despite therapeutic advances, treating advanced HCC remains challenging, emphasizing the need for continued efforts in prevention, early detection, and development of treatments to improve prognosis and long-term survival.
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Affiliation(s)
- Fei Feng
- Ultrasound Medicine, The First Hospital of Lanzhou University, Lanzhou, China,
| | - Yue Zhao
- Department of Gastroenterology, The First Hospital of Lanzhou University, Key Laboratory for Gastrointestinal Disease of Gansu Province, Lanzhou, China
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Yakout AA, Alshutairi AM, Albishri HM, Alshitari WH, Basha MT. Cu-nanoparticles@ graphene nanocomposite: A robust and efficient nanocomposite for micro-solid phase extraction of trace aflatoxins in different foodstuffs. Food Chem 2024; 440:138239. [PMID: 38154278 DOI: 10.1016/j.foodchem.2023.138239] [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: 08/28/2023] [Revised: 12/05/2023] [Accepted: 12/18/2023] [Indexed: 12/30/2023]
Abstract
Cu-nanoparticles-immobilized graphene (Cu@G) nanocomposite was fabricated in this study by reducing Cu(II) ions in the presence of graphene oxide using a simple chemical reduction step. Cu@G nanocomposite was applied as a sorbent for the SPE of four aflatoxins (AFs). A reusable syringe was filled with the fabricated nanocomposite and used as a sorbent for the micro-solid phase extraction of four AFs (AFB1, AFB2, AFG1, AFG2). The impact of different analytical factors was fully investigated and optimized. Excellent recoveries, ranging from 92.0 to 108.5 %, were detected when evaluating target AFs in samples of rice, maize, and pistachio. The LOD, LOQ, and linear ranges were attained under optimal circumstances in the ranges of 0.0062 µg kg-1, 0.0192 µg kg-1, and 0.0-20 µg kg-1, respectively. The discovered approach provided the dual benefits of a high enrichment capability of Cu-nanoparticles via AFs complexation and a huge porosity of graphene sheets.
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Affiliation(s)
- Amr A Yakout
- Chemistry Department, College of Science, University of Jeddah, Saudi Arabia; Chemistry Department, Faculty of Science, Alexandria University, Alexandria, Egypt.
| | - Adel M Alshutairi
- Saudi Food and Drug Authority, Saudi Arabia; Department of Chemistry, Faculty of Science, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Hassan M Albishri
- Department of Chemistry, Faculty of Science, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Wael H Alshitari
- Chemistry Department, College of Science, University of Jeddah, Saudi Arabia
| | - Maram T Basha
- Chemistry Department, College of Science, University of Jeddah, Saudi Arabia
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11
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Jin J, Huangfu B, Xing F, Xu W, He X. Combined exposure to deoxynivalenol facilitates lipid metabolism disorder in high-fat-diet-induced obesity mice. ENVIRONMENT INTERNATIONAL 2023; 182:108345. [PMID: 38008010 DOI: 10.1016/j.envint.2023.108345] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/15/2023] [Revised: 11/15/2023] [Accepted: 11/20/2023] [Indexed: 11/28/2023]
Abstract
Deoxynivalenol (DON) is a trichothecene toxin that mainly produced by strains of Fusarium spp. DON contamination is widely distributed and is a global food safety threat. Existing studies have expounded its harmful effects on growth inhibition, endocrine disruption, immune function impairment, and reproductive toxicity. In energy metabolism, DON suppresses appetite, reduces body weight, triggers lipid oxidation, and negatively affects cholesterol and fatty acid homeostasis. In this study, high-fat diet (HFD) induced obese C57BL/6J mice were orally treated with 0.1 mg/kg bw/d and 1.0 mg/kg bw/d DON for 4 weeks. The lipid metabolism of mice and the molecular mechanisms were explored. The data showed that although DON reduced body weight and fat mass in HFD mice, it significantly increased their serum triglyceride concentrations, disturbance of serum lipid metabolites, impaired glucose, and resulted in insulin intolerance in mice. In addition, the transcriptional and expression changes of lipid metabolism genes in the liver and epididymis (EP) adipose indicate that the DON-mediated increase in serum triglycerides is caused by lipoprotein lipase (LPL) inhibition in EP adipose. Furthermore, DON down-regulates the expression of LPL through the PPARγ signaling pathway in EP adipose. These results are further confirmed by the serum lipidomics analysis. In conclusion, DON acts on the PPARγ pathway of white adipose to inhibit the expression of LPL, mediate the increase of serum triglyceride in obese mice, disturb the homeostasis of lipid metabolism, and increase the risk of cardiovascular disease. This study reveals the interference mechanism of DON on lipid metabolism in obese mice and provides a theoretical basis for its toxic effect in obese individuals.
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Affiliation(s)
- Jing Jin
- Institute of Food Science and Technology, Chinese Academy of Agricultural Sciences/Key Laboratory of Agro-Products Quality and Safety Control in Storage and Transport Process, Ministry of Agriculture and Rural Affairs of P.R. China, Beijing 100193, PR China
| | - Bingxin Huangfu
- Key Laboratory of Precision Nutrition and Food Quality, Beijing Laboratory for Food Quality and Safety, College of Food Science and Nutritional Engineering, Department of Nutrition and Health, China Agricultural University, Beijing 100083, PR China
| | - Fuguo Xing
- Institute of Food Science and Technology, Chinese Academy of Agricultural Sciences/Key Laboratory of Agro-Products Quality and Safety Control in Storage and Transport Process, Ministry of Agriculture and Rural Affairs of P.R. China, Beijing 100193, PR China.
| | - Wentao Xu
- Key Laboratory of Precision Nutrition and Food Quality, Beijing Laboratory for Food Quality and Safety, College of Food Science and Nutritional Engineering, Department of Nutrition and Health, China Agricultural University, Beijing 100083, PR China
| | - Xiaoyun He
- Key Laboratory of Precision Nutrition and Food Quality, Beijing Laboratory for Food Quality and Safety, College of Food Science and Nutritional Engineering, Department of Nutrition and Health, China Agricultural University, Beijing 100083, PR China.
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12
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Houldcroft CJ, Underdown S. Infectious disease in the Pleistocene: Old friends or old foes? AMERICAN JOURNAL OF BIOLOGICAL ANTHROPOLOGY 2023; 182:513-531. [PMID: 38006200 DOI: 10.1002/ajpa.24737] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/12/2022] [Revised: 03/01/2023] [Accepted: 03/14/2023] [Indexed: 11/26/2023]
Abstract
The impact of endemic and epidemic disease on humans has traditionally been seen as a comparatively recent historical phenomenon associated with the Neolithisation of human groups, an increase in population size led by sedentarism, and increasing contact with domesticated animals as well as species occupying opportunistic symbiotic and ectosymbiotic relationships with humans. The orthodox approach is that Neolithisation created the conditions for increasing population size able to support a reservoir of infectious disease sufficient to act as selective pressure. This orthodoxy is the result of an overly simplistic reliance on skeletal data assuming that no skeletal lesions equated to a healthy individual, underpinned by the assumption that hunter-gatherer groups were inherently healthy while agricultural groups acted as infectious disease reservoirs. The work of van Blerkom, Am. J. Phys. Anthropol., vol. suppl 37 (2003), Wolfe et al., Nature, vol. 447 (2007) and Houldcroft and Underdown, Am. J. Phys. Anthropol., vol. 160, (2016) has changed this landscape by arguing that humans and pathogens have long been fellow travelers. The package of infectious diseases experienced by our ancient ancestors may not be as dissimilar to modern infectious diseases as was once believed. The importance of DNA, from ancient and modern sources, to the study of the antiquity of infectious disease, and its role as a selective pressure cannot be overstated. Here we consider evidence of ancient epidemic and endemic infectious diseases with inferences from modern and ancient human and hominin DNA, and from circulating and extinct pathogen genomes. We argue that the pandemics of the past are a vital tool to unlock the weapons needed to fight pandemics of the future.
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Affiliation(s)
| | - Simon Underdown
- Human Origins and Palaeoenvironmental Research Group, School of Social Sciences, Oxford Brookes University, Oxford, UK
- Center for Microbial Ecology and Genomics, Department of Biochemistry, Genetics and Microbiology, University of Pretoria, Pretoria, South Africa
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13
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Singal AG, Kanwal F, Llovet JM. Global trends in hepatocellular carcinoma epidemiology: implications for screening, prevention and therapy. Nat Rev Clin Oncol 2023; 20:864-884. [PMID: 37884736 DOI: 10.1038/s41571-023-00825-3] [Citation(s) in RCA: 287] [Impact Index Per Article: 143.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/25/2023] [Indexed: 10/28/2023]
Abstract
Hepatocellular carcinoma (HCC) mortality rates are increasing globally, and particularly in the Western world. Cirrhosis remains the predominant risk factor for HCC. However, epidemiological shifts in the incidence of HCC from patients with virus-related liver disease to those with non-viral aetiologies, including alcohol-associated and metabolic dysfunction-associated steatotic liver disease, have important implications for prevention, surveillance and treatment. Hepatitis B vaccination and antiviral therapy for hepatitis B and C are effective for primary prevention of virus-related HCCs, but chemoprevention strategies for non-viral liver disease remain an unmet need. Emerging data suggest associations between aspirin, statins, metformin and coffee and reduced HCC incidence, although none has been proved to be causally related. Secondary prevention of HCC via semi-annual surveillance is associated with improvements in early detection and thus reduced mortality; however, current tools, including abdominal ultrasonography, have suboptimal sensitivity for the detection of early stage HCC, particularly in patients with obesity and/or non-viral liver disease. Promising blood-based or imaging-based surveillance strategies are emerging, although these approaches require further validation before adoption in clinical practice. In the interim, efforts should be focused on maximizing use of the existing surveillance tools given their prevalent underuse globally. Remarkable advances have been made in the treatment of HCC, including expanded eligibility for surgical therapies, improved patient selection for locoregional treatments and increased systemic treatment options, including immune-checkpoint inhibitors. In this Review, we discuss trends in the epidemiology of HCC and their implications for screening, prevention and therapy.
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Affiliation(s)
- Amit G Singal
- Division of Digestive and Liver Diseases, Department of Internal Medicine, UT Southwestern Medical Center, Dallas, TX, USA.
| | - Fasiha Kanwal
- Section of Gastroenterology and Hepatology and Health Services Research, Department of Medicine, Baylor College of Medicine, Houston, TX, USA
- Section of Health Services Research, Department of Medicine, Baylor College of Medicine, Houston, TX, USA
- VA Health Services Research & Development Center for Innovations in Quality, Effectiveness, and Safety (IQuESt), Houston, TX, USA
- Michael E. DeBakey Veterans Affairs Medical Center, Houston, TX, USA
| | - Josep M Llovet
- Mount Sinai Liver Cancer Program, Division of Liver Diseases, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Translational Research in Hepatic Oncology, Liver Unit, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clinic, University of Barcelona, Barcelona, Spain
- Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain
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14
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Jin J, Kouznetsova VL, Kesari S, Tsigelny IF. Synergism in actions of HBV with aflatoxin in cancer development. Toxicology 2023; 499:153652. [PMID: 37858775 DOI: 10.1016/j.tox.2023.153652] [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: 08/17/2023] [Revised: 09/30/2023] [Accepted: 10/16/2023] [Indexed: 10/21/2023]
Abstract
Aflatoxin B1 (AFB1) is a fungal metabolite found in animal feeds and human foods. It is one of the most toxic and carcinogenic of aflatoxins and is classified as a Group 1 carcinogen. Dietary exposure to AFB1 and infection with chronic Hepatitis B Virus (HBV) make up two of the major risk factors for hepatocellular carcinoma (HCC). These two major risk factors raise the probability of synergism between the two agents. This review proposes some collaborative molecular mechanisms underlying the interaction between AFB1 and HBV in accelerating or magnifying the effects of HCC. The HBx viral protein is one of the main viral proteins of HBV and has many carcinogenic qualities that are involved with HCC. AFB1, when metabolized by CYP450, becomes AFB1-exo-8,9-epoxide (AFBO), an extremely toxic compound that can form adducts in DNA sequences and induce mutations. With possible synergisms that exist between HBV and AFB1 in mind, it is best to treat both agents simultaneously to reduce the risk by HCC.
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Affiliation(s)
- Joshua Jin
- IUL Scientific Program, San Diego, CA, USA
| | - Valentina L Kouznetsova
- San Diego Supercomputer Center, University of California at San Diego, La Jolla, CA, USA; BiAna, La Jolla, CA, USA; Curescience Institute, San Diego, CA, USA
| | | | - Igor F Tsigelny
- San Diego Supercomputer Center, University of California at San Diego, La Jolla, CA, USA; BiAna, La Jolla, CA, USA; Curescience Institute, San Diego, CA, USA; Department of Neurosciences, University of California at San Diego, La Jolla, CA, USA.
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15
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Schiffman M, Mirabello L, Egemen D, Befano B, Xiao Y, Wentzensen N, Raine-Bennett T, Nayar R, Cheung LC, Rositch A, Beaty T, Perkins RB, de Sanjose S, Lorey T, Castle PE, Burk RD. The combined finding of HPV 16, 18, or 45 and cytologic Atypical Glandular Cells (AGC) indicates a greatly elevated risk of in situ and invasive cervical adenocarcinoma. Gynecol Oncol 2023; 174:253-261. [PMID: 37243996 PMCID: PMC11089431 DOI: 10.1016/j.ygyno.2023.05.011] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2023] [Revised: 05/10/2023] [Accepted: 05/12/2023] [Indexed: 05/29/2023]
Abstract
BACKGROUND Cervical screening has not effectively controlled cervical adenocarcinoma (AC). Human papillomavirus (HPV) testing is recommended for cervical screening but the optimal management of HPV-positive individuals to prevent AC remains a question. Cytology and HPV typing are two triage options to predict the risk of AC. We combined two potential biomarkers (atypical glandular cell, AGC, cytology and HPV-types 16, 18, or 45) to assess their joint effect on detecting AC. METHODS Kaiser Permanente Northern California (KPNC) used triennial co-testing with cytology and HPV testing (positive/negative) for routine cervical screening between 2003 and 2020. HPV typing of a sample of residual HPV test specimens was performed on a separate cohort selected from KPNC (Persistence and Progression, PaP, cohort). We compared risk of prevalent and incident histologic AC/AIS (adenocarcinoma in situ) associated with preceding combinations of cytologic results and HPV typing. Risk of squamous cell cancer (SCC)/cervical intraepithelial neoplasia grade 3 (CIN3) (SCC/CIN3) was also included for comparison. RESULTS Among HPV-positive individuals in PaP cohort, 99% of prevalent AC and 96% of AIS were linked to HPV-types 16, 18, or 45 (denoted HPV 16/18/45). Although rare (0.09% of screening population), the concurrent detection of HPV 16/18/45 with AGC cytology predicted a highly elevated relative risk of underlying histologic AC/AIS; the absolute risk of diagnosing AC/AIS was 12% and odds ratio (OR) was 1341 (95%CI:495-3630) compared to patients with other high-risk HPV types and normal cytology. Cumulatively (allowing non-concurrent results), approximately one-third of the AC/AIS cases ever had HPV 16/18/45 and AGC cytology (OR = 1785; 95%CI:872-3656). AGC was not as strongly associated with SCC/CIN3. CONCLUSION Detection of HPV 16/18/45 positivity elevates risk of adenocarcinoma, particularly if AGC cytology is also found.
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Affiliation(s)
- Mark Schiffman
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Rockville, MD, USA.
| | - Lisa Mirabello
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Rockville, MD, USA
| | - Didem Egemen
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Rockville, MD, USA
| | - Brian Befano
- Information Management Services Inc, Calverton, MD, USA
| | - Yanzi Xiao
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Rockville, MD, USA
| | - Nicolas Wentzensen
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Rockville, MD, USA
| | - Tina Raine-Bennett
- Women's Health Research Institute, Division of Research, Kaiser Permanente Northern California, Oakland, CA, USA
| | - Ritu Nayar
- Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
| | - Li C Cheung
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Rockville, MD, USA
| | - Anne Rositch
- Department of Epidemiology, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD, USA
| | - Terri Beaty
- Department of Epidemiology, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD, USA
| | - Rebecca B Perkins
- Boston University Chobanian and Avedisian School of Medicine, Boston Medical Center, Boston, MA, USA
| | - Silvia de Sanjose
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Rockville, MD, USA; ISGlobal, Barcelona, Spain
| | - Thomas Lorey
- Regional Laboratory, Kaiser Permanente Northern California, Oakland, CA, USA
| | - Philip E Castle
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Rockville, MD, USA; Division of Cancer Prevention, National Cancer Institute, National Institutes of Health, Rockville, MD, USA
| | - Robert D Burk
- Departments of Pediatrics, Microbiology & Immunology, Epidemiology & Population Health, and Obstetrics, Gynecology & Women's Health, Albert Einstein College of Medicine, Bronx, NY, USA
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16
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Jaruga P, Tomar R, Kant M, Vartanian V, Sexton B, Rizzo CJ, Turesky RJ, Stone MP, Lloyd RS, Dizdaroglu M. Synthesis and Characterization of 15N 5-Labeled Aflatoxin B 1-Formamidopyrimidines and Aflatoxin B 1-N7-Guanine from a Partial Double-Stranded Oligodeoxynucleotide as Internal Standards for Mass Spectrometric Measurements. ACS OMEGA 2023; 8:14841-14854. [PMID: 37125130 PMCID: PMC10134230 DOI: 10.1021/acsomega.3c01328] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/27/2023] [Accepted: 03/20/2023] [Indexed: 05/03/2023]
Abstract
Aflatoxin B1 (AFB1) exposure through contaminated food is a primary contributor to hepatocellular carcinogenesis worldwide. Hepatitis B viral infections in livers dramatically increase the carcinogenic potency of AFB1 exposures. Liver cytochrome P450 oxidizes AFB1 to the epoxide, which in turn reacts with N7-guanine in DNA, producing the cationic trans-8,9-dihydro-8-(N7-guanyl)-9-hydroxyaflatoxin B1 adduct (AFB1-N7-Gua). The opening of the imidazole ring of AFB1-N7-Gua under physiological conditions causes the formation of the cis- and trans-diastereomers of 8,9-dihydro-8-(2,6-diamino-4-oxo-3,4-dihydropyrimid-5-yl-formamido)-9-hydroxyaflatoxin B1 (AFB1-FapyGua). These adducts primarily lead to G → T mutations, with AFB1-FapyGua being significantly more mutagenic than AFB1-N7-Gua. The unequivocal identification and accurate quantification of these AFB1-Gua adducts as biomarkers are essential for a fundamental understanding and prevention of AFB1-induced hepatocellular carcinogenesis. Among a variety of analytical techniques used for this purpose, liquid chromatography-tandem mass spectrometry, with the use of the stable isotope-labeled analogues of AFB1-FapyGua and AFB1-N7-Gua as internal standards, provides the greatest accuracy and sensitivity. cis-AFB1-FapyGua-15N5, trans-AFB1-FapyGua-15N5, and AFB1-N7-Gua-15N5 have been synthesized and used successfully as internal standards. However, the availability of these standards from either academic institutions or commercial sources ceased to exist. Thus, quantitative genomic data regarding AFB1-induced DNA damage in animal models and humans remain challenging to obtain. Previously, AFB1-N7-Gua-15N5 was prepared by reacting AFB1-exo-8,9-epoxide with the uniformly 15N5-labeled DNA isolated from algae grown in a pure 15N-environment, followed by alkali treatment, resulting in the conversion of AFB1-N7-Gua-15N5 to AFB1-FapyGua-15N5. In the present work, we used a different and simpler approach to synthesize cis-AFB1-FapyGua-15N5, trans-AFB1-FapyGua-15N5, and AFB1-N7-Gua-15N5 from a partial double-stranded 11-mer Gua-15N5-labeled oligodeoxynucleotide, followed by isolation and purification. We also show the validation of these 15N5-labeled standards for the measurement of cis-AFB1-FapyGua, trans-AFB1-FapyGua, and AFB1-N7-Gua in DNA of livers of AFB1-treated mice.
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Affiliation(s)
- Pawel Jaruga
- Biomolecular
Measurement Division, National Institute
of Standards and Technology, Gaithersburg, Maryland 20899, United States
| | - Rachana Tomar
- Department
of Chemistry, Vanderbilt Ingram Cancer Center, Vanderbilt University, Nashville, Tennessee 37235, United States
| | - Melis Kant
- Biomolecular
Measurement Division, National Institute
of Standards and Technology, Gaithersburg, Maryland 20899, United States
| | - Vladimir Vartanian
- Oregon
Institute of Occupational Health Sciences, Oregon Health & Science University, Portland, Oregon 97239, United States
| | - Benjamin Sexton
- Department
of Chemistry, Vanderbilt Ingram Cancer Center, Vanderbilt University, Nashville, Tennessee 37235, United States
| | - Carmelo J. Rizzo
- Department
of Chemistry, Vanderbilt Ingram Cancer Center, Vanderbilt University, Nashville, Tennessee 37235, United States
| | - Robert J. Turesky
- Masonic
Cancer Center, University of Minnesota, Minneapolis, Minnesota 55455, United States
| | - Michael P. Stone
- Department
of Chemistry, Vanderbilt Ingram Cancer Center, Vanderbilt University, Nashville, Tennessee 37235, United States
| | - R. Stephen Lloyd
- Oregon
Institute of Occupational Health Sciences, Oregon Health & Science University, Portland, Oregon 97239, United States
| | - Miral Dizdaroglu
- Biomolecular
Measurement Division, National Institute
of Standards and Technology, Gaithersburg, Maryland 20899, United States
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17
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Hartmann P, Schnabl B. Fungal infections and the fungal microbiome in hepatobiliary disorders. J Hepatol 2023; 78:836-851. [PMID: 36565724 PMCID: PMC10033447 DOI: 10.1016/j.jhep.2022.12.006] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/11/2022] [Revised: 12/05/2022] [Accepted: 12/07/2022] [Indexed: 12/24/2022]
Abstract
Liver and biliary diseases affect more than a billion people worldwide, with high associated morbidity and mortality. The impact of the intestinal bacterial microbiome on liver diseases has been well established. However, the fungal microbiome, or mycobiome, has been overlooked for a long time. Recently, several studies have shed light on the role of the mycobiome in the development and progression of hepatobiliary diseases. In particular, the fungal genus Candida has been found to be involved in the pathogenesis of multiple hepatobiliary conditions. Herein, we compare colonisation and infection, describe mycobiome findings in the healthy state and across the various hepatobiliary conditions, and point toward communalities. We detail how quantitation of immune responses to fungal antigens can be employed to predict disease severity, e.g. using antibodies to Saccharomyces cerevisiae or specific anti-Candida albicans antibodies. We also show how fungal products (e.g. beta-glucans, candidalysin) activate the host's immune system to exacerbate liver and biliary diseases. Finally, we describe how the gut mycobiome can be modulated to ameliorate hepatobiliary conditions.
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Affiliation(s)
- Phillipp Hartmann
- Department of Medicine, University of California San Diego, La Jolla, CA, USA; Department of Pediatrics, University of California San Diego, La Jolla, CA, USA; Division of Gastroenterology, Hepatology & Nutrition, Rady Children's Hospital San Diego, San Diego, CA, USA
| | - Bernd Schnabl
- Department of Medicine, University of California San Diego, La Jolla, CA, USA; Department of Medicine, VA San Diego Healthcare System, San Diego, CA, USA.
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18
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Zou G, Park JI. Wnt signaling in liver regeneration, disease, and cancer. Clin Mol Hepatol 2023; 29:33-50. [PMID: 35785913 PMCID: PMC9845677 DOI: 10.3350/cmh.2022.0058] [Citation(s) in RCA: 34] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/01/2022] [Accepted: 06/30/2022] [Indexed: 02/02/2023] Open
Abstract
The liver exhibits the highest recovery rate from acute injuries. However, in chronic liver disease, the long-term loss of hepatocytes often leads to adverse consequences such as fibrosis, cirrhosis, and liver cancer. The Wnt signaling plays a pivotal role in both liver regeneration and tumorigenesis. Therefore, manipulating the Wnt signaling has become an attractive approach to treating liver disease, including cancer. Nonetheless, given the crucial roles of Wnt signaling in physiological processes, blocking Wnt signaling can also cause several adverse effects. Recent studies have identified cancer-specific regulators of Wnt signaling, which would overcome the limitation of Wnt signaling target approaches. In this review, we discussed the role of Wnt signaling in liver regeneration, precancerous lesion, and liver cancer. Furthermore, we summarized the basic and clinical approaches of Wnt signaling blockade and proposed the therapeutic prospects of cancer-specific Wnt signaling blockade for liver cancer treatment.
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Affiliation(s)
- Gengyi Zou
- Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA,Corresponding author : Gengyi Zou Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, 6565 MD Anderson Blvd Unit 1054, Houston, TX 77030, USA Tel: +1-713-792-3659, Fax: +1-713-794-5369, E-mail:
| | - Jae-Il Park
- Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA,Genetics and Epigenetics Program, The University of Texas MD Anderson Cancer Center Graduate School of Biomedical Sciences, Houston, TX, USA,Jae-Il Park Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, 6565 MD Anderson Blvd. Unit 1052, Houston, TX 77030, USA Tel: +1-713-792-3659, Fax: +1-713-794-5369, E-mail:
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19
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Anticarcinogenic Effects of Isothiocyanates on Hepatocellular Carcinoma. Int J Mol Sci 2022; 23:ijms232213834. [PMID: 36430307 PMCID: PMC9693344 DOI: 10.3390/ijms232213834] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2022] [Revised: 11/02/2022] [Accepted: 11/08/2022] [Indexed: 11/12/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer, accounting for about 90% of cases. Sorafenib, lenvatinib, and the combination of atezolizumab and bevacizumab are considered first-line treatments for advanced HCC. However, clinical application of these drugs has also caused some adverse reactions such as hypertension, elevated aspartate aminotransferases, and proteinuria. At present, natural products and their derivatives have drawn more and more attention due to less side effects as cancer treatments. Isothiocyanates (ITCs) are one type of hydrolysis products from glucosinolates (GLSs), secondary plant metabolites found exclusively in cruciferous vegetables. Accumulating evidence from encouraging in vitro and in vivo animal models has demonstrated that ITCs have multiple biological activities, especially their potentially health-promoting activities (antibacterial, antioxidant, and anticarcinogenic effects). In this review, we aim to comprehensively summarize the chemopreventive, anticancer, and chemosensitizative effects of ITCs on HCC, and explain the underlying molecular mechanisms.
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20
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Lo CH, Wu DC, Jao SW, Wu CC, Lin CY, Chuang CH, Lin YB, Chen CH, Chen YT, Chen JH, Hsiao KH, Chen YJ, Chen YT, Wang JY, Li LH. Enrichment of Prevotella intermedia in human colorectal cancer and its additive effects with Fusobacterium nucleatum on the malignant transformation of colorectal adenomas. J Biomed Sci 2022; 29:88. [PMID: 36303164 PMCID: PMC9615364 DOI: 10.1186/s12929-022-00869-0] [Citation(s) in RCA: 40] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2022] [Accepted: 10/18/2022] [Indexed: 12/02/2022] Open
Abstract
BACKGROUND Owing to the heterogeneity of microbiota among individuals and populations, only Fusobacterium nucleatum and Bacteroides fragilis have been reported to be enriched in colorectal cancer (CRC) in multiple studies. Thus, the discovery of additional bacteria contributing to CRC development in various populations can be expected. We aimed to identify bacteria associated with the progression of colorectal adenoma to carcinoma and determine the contribution of these bacteria to malignant transformation in patients of Han Chinese origin. METHODS Microbiota composition was determined through 16S rRNA V3-V4 amplicon sequencing of autologous adenocarcinomas, adenomatous polyps, and non-neoplastic colon tissue samples (referred to as "tri-part samples") in patients with CRC. Enriched taxa in adenocarcinoma tissues were identified through pairwise comparison. The abundance of candidate bacteria was quantified through genomic quantitative polymerase chain reaction (qPCR) in tissue samples from 116 patients. Associations of candidate bacteria with clinicopathological features and genomic and genetic alterations were evaluated through odds ratio tests. Additionally, the effects of candidate bacteria on CRC cell proliferation, migration, and invasion were evaluated through the co-culture of CRC cells with bacterial cells or with conditioned media from bacteria. RESULTS Prevotella intermedia was overrepresented in adenocarcinomas compared with paired adenomatous polyps. Furthermore, co-abundance of P. intermedia and F. nucleatum was observed in tumor tissues. More notably, the coexistence of these two bacteria in adenocarcinomas was associated with lymph node involvement and distant metastasis. These two bacteria also exerted additive effects on the enhancement of the migration and invasion abilities of CRC cells. Finally, conditioned media from P. intermedia promoted the migration and invasion of CRC cells. CONCLUSION This report is the first to demonstrate that P. intermedia is enriched in colorectal adenocarcinoma tissues and enhances the migration and invasion abilities of CRC cells. Moreover, P. intermedia and F. nucleatum exert additive effects on the malignant transformation of colorectal adenomas into carcinomas. These findings can be used to identify patients at a high risk of malignant transformation of colorectal adenomas or metastasis of CRC, and they can accordingly be provided optimal clinical management.
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Affiliation(s)
- Chia-Hui Lo
- Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan
| | - Deng-Chyang Wu
- Division of Gastroenterology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
- School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
- Regenerative Medicine and Cell Therapy Research Center, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Shu-Wen Jao
- Division of Colon and Rectal Surgery, Tri-Service General Hospital, Taipei, Taiwan
| | - Chang-Chieh Wu
- Division of Colon and Rectal Surgery, Tri-Service General Hospital, Taipei, Taiwan
| | - Chung-Yen Lin
- Institute of Information Science, Academia Sinica, Taipei, Taiwan
| | | | - Ya-Bo Lin
- Institute of Information Science, Academia Sinica, Taipei, Taiwan
| | - Chien-Hsiun Chen
- Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan
| | - Ying-Ting Chen
- Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan
| | - Jiann-Hwa Chen
- Scool of Medicine, Tzu Chi General Hospital, Taipei Branch, Taipei, Taiwan
| | - Koung-Hung Hsiao
- Department of Colorectal Surgery, Tzu Chi General Hospital, Taipei Branch, Taipei, Taiwan
| | - Ying-Ju Chen
- Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan
| | - Yuan-Tsong Chen
- Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan
| | - Jaw-Yuan Wang
- Division of Colorectal Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan.
- Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
- Pingtung Hospital, Ministry of Health and Welfare, Pingtung, Taiwan.
| | - Ling-Hui Li
- Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.
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21
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Dai C, Tian E, Hao Z, Tang S, Wang Z, Sharma G, Jiang H, Shen J. Aflatoxin B1 Toxicity and Protective Effects of Curcumin: Molecular Mechanisms and Clinical Implications. Antioxidants (Basel) 2022; 11:antiox11102031. [PMID: 36290754 PMCID: PMC9598162 DOI: 10.3390/antiox11102031] [Citation(s) in RCA: 52] [Impact Index Per Article: 17.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2022] [Revised: 10/09/2022] [Accepted: 10/10/2022] [Indexed: 11/26/2022] Open
Abstract
One of the most significant classes of mycotoxins, aflatoxins (AFTs), can cause a variety of detrimental outcomes, including cancer, hepatitis, aberrant mutations, and reproductive issues. Among the 21 identified AFTs, aflatoxin B1 (AFB1) is the most harmful to humans and animals. The mechanisms of AFB1-induced toxicity are connected to the generation of excess reactive oxygen species (ROS), upregulation of CYP450 activities, oxidative stress, lipid peroxidation, apoptosis, mitochondrial dysfunction, autophagy, necrosis, and inflammatory response. Several signaling pathways, including p53, PI3K/Akt/mTOR, Nrf2/ARE, NF-κB, NLRP3, MAPKs, and Wnt/β-catenin have been shown to contribute to AFB1-mediated toxic effects in mammalian cells. Curcumin, a natural product with multiple therapeutic activities (e.g., anti-inflammatory, antioxidant, anticancer, and immunoregulation activities), could revise AFB1-induced harmful effects by targeting these pathways. Therefore, the potential therapeutic use of curcumin against AFB1-related side effects and the underlying molecular mechanisms are summarized. This review, in our opinion, advances significant knowledge, sparks larger discussions, and drives additional improvements in the hazardous examination of AFTs and detoxifying the application of curcumin.
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Affiliation(s)
- Chongshan Dai
- Department of Veterinary Pharmacology and Toxicology, College of Veterinary Medicine, China Agricultural University, Beijing 100193, China
- Key Biology Laboratory of Chinese Veterinary Medicine, Ministry of Agriculture and Rural Affairs, Beijing 100193, China
- Correspondence:
| | - Erjie Tian
- College of Animal Science and Technology, Henan University of Science and Technology, Luoyang 471023, China
| | - Zhihui Hao
- Department of Veterinary Pharmacology and Toxicology, College of Veterinary Medicine, China Agricultural University, Beijing 100193, China
- Key Biology Laboratory of Chinese Veterinary Medicine, Ministry of Agriculture and Rural Affairs, Beijing 100193, China
| | - Shusheng Tang
- Department of Veterinary Pharmacology and Toxicology, College of Veterinary Medicine, China Agricultural University, Beijing 100193, China
| | - Zhanhui Wang
- Department of Veterinary Pharmacology and Toxicology, College of Veterinary Medicine, China Agricultural University, Beijing 100193, China
| | - Gaurav Sharma
- Advanced Imaging Research Center, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Haiyang Jiang
- Department of Veterinary Pharmacology and Toxicology, College of Veterinary Medicine, China Agricultural University, Beijing 100193, China
| | - Jianzhong Shen
- Department of Veterinary Pharmacology and Toxicology, College of Veterinary Medicine, China Agricultural University, Beijing 100193, China
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22
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Kobets T, Smith BPC, Williams GM. Food-Borne Chemical Carcinogens and the Evidence for Human Cancer Risk. Foods 2022; 11:2828. [PMID: 36140952 PMCID: PMC9497933 DOI: 10.3390/foods11182828] [Citation(s) in RCA: 27] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2022] [Revised: 09/07/2022] [Accepted: 09/08/2022] [Indexed: 11/16/2022] Open
Abstract
Commonly consumed foods and beverages can contain chemicals with reported carcinogenic activity in rodent models. Moreover, exposures to some of these substances have been associated with increased cancer risks in humans. Food-borne carcinogens span a range of chemical classes and can arise from natural or anthropogenic sources, as well as form endogenously. Important considerations include the mechanism(s) of action (MoA), their relevance to human biology, and the level of exposure in diet. The MoAs of carcinogens have been classified as either DNA-reactive (genotoxic), involving covalent reaction with nuclear DNA, or epigenetic, involving molecular and cellular effects other than DNA reactivity. Carcinogens are generally present in food at low levels, resulting in low daily intakes, although there are some exceptions. Carcinogens of the DNA-reactive type produce effects at lower dosages than epigenetic carcinogens. Several food-related DNA-reactive carcinogens, including aflatoxins, aristolochic acid, benzene, benzo[a]pyrene and ethylene oxide, are recognized by the International Agency for Research on Cancer (IARC) as causes of human cancer. Of the epigenetic type, the only carcinogen considered to be associated with increased cancer in humans, although not from low-level food exposure, is dioxin (TCDD). Thus, DNA-reactive carcinogens in food represent a much greater risk than epigenetic carcinogens.
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Affiliation(s)
- Tetyana Kobets
- Department of Pathology, Microbiology and Immunology, New York Medical College, Valhalla, NY 10595, USA
| | - Benjamin P. C. Smith
- Future Ready Food Safety Hub, Nanyang Technological University, Singapore 639798, Singapore
| | - Gary M. Williams
- Department of Pathology, Microbiology and Immunology, New York Medical College, Valhalla, NY 10595, USA
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23
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Paturel A, Hall J, Chemin I. Poly(ADP-Ribose) Polymerase Inhibition as a Promising Approach for Hepatocellular Carcinoma Therapy. Cancers (Basel) 2022; 14:3806. [PMID: 35954469 PMCID: PMC9367559 DOI: 10.3390/cancers14153806] [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: 07/11/2022] [Revised: 08/02/2022] [Accepted: 08/03/2022] [Indexed: 11/17/2022] Open
Abstract
Primary liver cancer is the sixth most common cancer in men and seventh in women, with hepatocellular carcinoma (HCC) being the most common form (75-85% of primary liver cancer cases) and the most frequent etiology being viral infections (HBV and HCV). In 2020, mortality represented 92% of the incidence-830,180 deaths for 905,677 new cases. Few treatment options exist for advanced or terminal-stage HCC, which will receive systemic therapy or palliative care. Although radiotherapy is used in the treatment of many cancers, it is currently not the treatment of choice for HCC, except in the palliative setting. However, as radiosensitizing drugs, such as inhibitors of DNA repair enzymes, could potentiate the effects of RT in HCC by exploiting the modulation of DNA repair processes found in this tumour type, RT and such drugs could provide a treatment option for HCC. In this review, we provide an overview of PARP1 involvement in DNA damage repair pathway and discuss its potential implication in HCC. In addition, the use of PARP inhibitors and PARP decoys is described for the treatment of HCC and, in particular, in HBV-related HCC.
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Affiliation(s)
| | | | - Isabelle Chemin
- Université de Lyon, Université Claude Bernard Lyon 1, INSERM, CNRS, Centre Léon Bérard, Centre De Recherche En Cancérologie De Lyon, 69008 Lyon, France
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24
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Kortei NK, Annan T, Boakye AA, Essuman EK, Tettey CO, Kyei-Baffour V. Aflatoxin M 1 exposure in a fermented millet-based milk beverage 'brukina' and its cancer risk characterization in Greater Accra, Ghana. Sci Rep 2022; 12:12562. [PMID: 35869134 PMCID: PMC9307601 DOI: 10.1038/s41598-022-15157-y] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2021] [Accepted: 06/20/2022] [Indexed: 12/02/2022] Open
Abstract
Brukina is a millet based fermented milk product which is consumed as a beverage in Ghana. It is however prone to aflatoxin M1 (AFM1) contamination, which is a serious health challenge for low and middle-income countries in subtropical regions. This study aimed at evaluating AFM1 levels and cancer risks associated with brukina (n = 150) sampled from different locations of the Greater Accra Region of Ghana. AFM1 were measured with High-Performance Liquid Chromatography (HPLC) connected to a Fluorescence Detector (FLD).Cancer risk assessments were also conducted using models prescribed by the Joint FAO/WHO Expert Committee on Additives (JECFA). Out of the 150 samples analyzed for AFM1, 80/150 (53%) tested positive between the range 0.00 ± 0.001-3.14 ± 0.77 µg/kg. Cancer risk assessments of AFM1 produced outcomes which ranged between 0.64 and 1.88 ng/kg bw/day, 0.31-9.40, 0.0323, and 1.94 × 10-3-0.06 for cases/100,000 person/yr for Estimated Daily Intake (EDI), Hazard Index (H.I), Average Potency, and Cancer Risks respectively for all age categories investigated. It was concluded that the consumption of brukina posed adverse health effects on the majority of the age categories in the different locations of Greater Accra Region since the calculated H.Is were greater than one (> 1). Therefore, contamination of brukina with AFM1 should be considered a high priority in public health and Ghana's cancer risk management actions.
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Affiliation(s)
- Nii Korley Kortei
- Department of Nutrition and Dietetics, School of Allied Health Sciences, University of Health and Allied Sciences, PMB 31, Ho, Ghana.
| | - Theophilus Annan
- Food Microbiology Division, Council for Scientific and Industrial Research- Food Research Institute, P. O. Box M20, Accra, Ghana
| | - Adjoa Agyemang Boakye
- Department of Biomedical Sciences, School of Basic and Biomedical Sciences, University of Health and Allied Sciences, PMB 31, Ho, Ghana
| | - Edward Ken Essuman
- Department of Nutrition and Dietetics, School of Allied Health Sciences, University of Health and Allied Sciences, PMB 31, Ho, Ghana
| | - Clement Okraku Tettey
- Department of Biomedical Sciences, School of Basic and Biomedical Sciences, University of Health and Allied Sciences, PMB 31, Ho, Ghana
| | - Vincent Kyei-Baffour
- Food Chemistry and Nutrition Research Division, Council for Scientific and Industrial Research-Food Research Institute, P. O. Box M20, Accra, Ghana
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25
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Ayoub WS, Jones PD, Yang JD, Martin P. Emerging drugs for the treatment of hepatocellular carcinoma. Expert Opin Emerg Drugs 2022; 27:141-149. [PMID: 35642526 DOI: 10.1080/14728214.2022.2083107] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/27/2023]
Abstract
INTRODUCTION Hepatocellular carcinoma (HCC) remains a leading cause of liver related mortality. Cirrhosis of any etiology is the major risk factor although HCC can develop in its absence in patients with Hepatitis B and increasingly in those with non-alcoholic fatty liver disease. When detected at an early stage, curative options include surgical resection, liver transplantation and/or ablative therapies. Unfortunately, most cases of HCC are recognized at an advanced state when options are limited and non-curative. However new systemic therapies with tyrosine kinase inhibitors and immunotherapy have expanded therapeutic options in advanced HCC. Advances in systemic therapy have given patients with advanced HCC hope and prolonged their survival. Ongoing trials addressing different combination therapies with checkpoint inhibitors, tyrosine kinase inhibitors (TKI) or anti-VEGF therapies are expected to further enhance the management of advanced HCC. AREAS COVERED We discuss recent data and ongoing research efforsts to improve the treatment of hepatocellular carcinoma with discussion of current and upcoming systemic therapy combining agents of different classes. EXPERT OPINION Sustemic therapy for HCC is in evolution. The inclusion of immunotherapy to systemic therapy has revolutionalized the field of HCC treatment. Identificantion of the appropriate combination and sequence of systemic therapy coupled with discovery of reliable HCC biomarkers will lead to improved survival and inidividulized HCC therapy.
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Affiliation(s)
- Walid S Ayoub
- Cedars-Sinai Medical Center, Los Angeles, United States
| | - Patricia D Jones
- University of Miami Miller School of Medicine, Miami, Florida, United States
| | - Ju Dong Yang
- Cedars-Sinai Medical Center, Los Angeles, United States
| | - Paul Martin
- University of Miami Miller School of Medicine, Miami, Florida, United States
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26
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Aflatoxin M1 Contamination of Ghanaian Traditional Soft Cottage Cheese (Wagashie) and Health Risks Associated with Its Consumption. J FOOD QUALITY 2022. [DOI: 10.1155/2022/7595545] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
Abstract
Wagashie is an unripened traditional cheese consumed in West Africa including Ghana. Being a milk product, it is unfortunately susceptible to aflatoxin M1 (AFM1) contamination, which is indeed a grave health challenge globally. This study evaluated AFM1 levels and health risk characterization associated with wagashie (n = 182) sampled from different locations in Ghana. AFM1 was measured with high-performance liquid chromatography with a fluorescence detector (HPLC-FLD). Risk assessments were also conducted using models prescribed by the Joint FAO/WHO Expert Committee on Food Additives (JECFA). Out of the 182 samples analyzed for AFM1, 93/182 (51.1%) tested positive between the range 0.00 ± 0.00–3.60 ± 0.99 µg/kg. Risk assessments of AFM1 using deterministic models produced outcomes that ranged between 0.11 and 3.60 ng/kg bw/day, 0.09–1.54, 0–0.0323 ng aflatoxins/kg bw/day, and 3.5 x 10−3 −0.06 cases/100,000 person/yr for estimated daily intake (EDI), margin of exposure (MOE), average potency, and cancer risks, respectively, for the age categories investigated. It was established that the consumption of wagashie posed adverse health effects on all age categories in the selected regions of the study because all calculated MOE values were less than 100,000. Therefore, contamination of wagashie with AFM1 should be a serious public health concern and as such considered a high precedence for Ghana’s risk management actions.
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27
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PINK1/Parkin-mediated mitophagy as a protective mechanism against AFB 1-induced liver injury in mice. Food Chem Toxicol 2022; 164:113043. [PMID: 35447291 DOI: 10.1016/j.fct.2022.113043] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2021] [Revised: 03/19/2022] [Accepted: 04/14/2022] [Indexed: 11/22/2022]
Abstract
Aflatoxin B1 (AFB1) can cause oxidative stress leading to mitochondrial damage and subsequent liver injury. Although it is well-known that damaged mitochondria are eliminated by PINK1/Parkin-mediated mitophagy, this mechanism has not yet been characterized in the context of AFB1-induced liver injury. In this study, male wild-type C57BL/6N mice were divided into groups 1-4, which were then orally administered 0, 0.5, 0.75, and 1 mg/kg body weight AFB1 for 28 d, respectively. Our results demonstrated that oxidative stress, NLRP3-inflammasome activation, and mitochondrial damage were dose-dependently augmented in AFB1-induced liver injury. Additionally, PINK1/Parkin-mediated mitophagy peaked in the groups that had received a mid-dose of AFB1 (0.75 mg/kg), which was attenuated slightly in high-dose groups. Afterward, we further characterized AFB1-induced liver injury by comparing wild-type C57BL/6N mice with Parkin knockout (Parkin-/-) mice. We found that the restricted mitophagy in Parkin-/- mice was associated with increased oxidative stress, NLRP3-inflammasome activation, mitochondrial damage, and liver injury. Taken together, these results indicate that PINK1/Parkin-mediated mitophagy plays an important role in attenuating AFB1-induced liver injury in mice.
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28
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Cisneros-Garza L, González-Huezo M, Moctezuma-Velázquez C, Ladrón de Guevara-Cetina L, Vilatobá M, García-Juárez I, Alvarado-Reyes R, Álvarez-Treviño G, Allende-Pérez S, Bornstein-Quevedo L, Calderillo-Ruiz G, Carrillo-Martínez M, Castillo-Barradas M, Cerda-Reyes E, Félix-Leyva J, Gabutti-Thomas J, Guerrero-Ixtlahuac J, Higuera-de-la-Tijera F, Huitzil-Meléndez D, Kimura-Hayama E, López-Hernández P, Malé-Velázquez R, Méndez-Sánchez N, Morales-Ruiz M, Ruíz-García E, Sánchez-Ávila J, Torrecillas-Torres L. The second Mexican consensus on hepatocellular carcinoma. Part I: Epidemiology and diagnosis. REVISTA DE GASTROENTEROLOGÍA DE MÉXICO (ENGLISH EDITION) 2022; 87:216-234. [DOI: 10.1016/j.rgmxen.2021.10.009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/04/2021] [Accepted: 10/21/2021] [Indexed: 12/24/2022] Open
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29
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Cisneros-Garza LE, González-Huezo MS, Moctezuma-Velázquez C, Ladrón de Guevara-Cetina L, Vilatobá M, García-Juárez I, Alvarado-Reyes R, Álvarez-Treviño GA, Allende-Pérez S, Bornstein-Quevedo L, Calderillo-Ruiz G, Carrillo-Martínez MA, Castillo-Barradas M, Cerda-Reyes E, Félix-Leyva JA, Gabutti-Thomas JA, Guerrero-Ixtlahuac J, Higuera-de-la-Tijera F, Huitzil-Meléndez D, Kimura-Hayama E, López-Hernández PA, Malé-Velázquez R, Méndez-Sánchez N, Morales-Ruiz MA, Ruíz-García E, Sánchez-Ávila JF, Torrecillas-Torres L. The second Mexican consensus on hepatocellular carcinoma. Part I: Epidemiology and diagnosis. REVISTA DE GASTROENTEROLOGIA DE MEXICO (ENGLISH) 2022; 87:216-234. [PMID: 35431142 DOI: 10.1016/j.rgmx.2021.10.002] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/04/2021] [Accepted: 10/21/2021] [Indexed: 01/04/2025]
Abstract
Hepatocellular carcinoma (HCC) is more frequently manifesting as one of the main complications of cirrhosis of the liver, its principal risk factor. There have been modifications in its incidence over the past decade, related to an epidemiologic transition in the etiology of cirrhosis, with a decrease in the prevalence of hepatitis C and an increase in nonalcoholic fatty liver disease (NAFLD) as a cause, as well as the development of HCC in the non-cirrhotic liver due to NAFLD. Genetic markers associated with the disease have been identified, and surveillance and diagnosis have improved. Regarding treatment, surgical techniques, in both resection and transplantation, have advanced and radiologic techniques, at the curative stage of the disease, have enhanced survival in those patients. And finally, there have been radical changes in the systemic approach, with much more optimistic expectations, when compared with the options available a decade ago. Therefore, the Asociación Mexicana de Hepatología decided to carry out the Second Mexican Consensus on Hepatocellular Carcinoma, which is an updated review of the available national and international evidence on the epidemiology, risk factors, surveillance, diagnosis, and treatment of the disease, to offer the Mexican physician current information on the different topics regarding hepatocellular carcinoma. In this first part of the document, the topics related to epidemiology and diagnosis are presented.
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Affiliation(s)
- L E Cisneros-Garza
- Hospital Christus Muguerza Alta Especialidad, Monterrey, Nuevo León, Mexico
| | | | - C Moctezuma-Velázquez
- Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico
| | | | - M Vilatobá
- Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico
| | - I García-Juárez
- Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico
| | | | - G A Álvarez-Treviño
- Unidad de Medicina de Alta Especialidad 25 IMSS, Monterrey, Nuevo León, Mexico
| | | | - L Bornstein-Quevedo
- InmunoQ, Laboratorio de Patología, Inmunohistoquímica y Biología Molecular, Mexico City, Mexico
| | | | | | | | | | | | - J A Gabutti-Thomas
- Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico
| | | | | | - D Huitzil-Meléndez
- Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico
| | | | - P A López-Hernández
- Unidad de Medicina de Alta Especialidad 25 IMSS, Monterrey, Nuevo León, Mexico
| | - R Malé-Velázquez
- Instituto de Salud Digestiva y Hepática SA de CV, Guadalajara, Jalisco, Mexico
| | | | - M A Morales-Ruiz
- Centro Oncológico Estatal Issemym, Toluca, Estado de México, Mexico
| | - E Ruíz-García
- Instituto Nacional de Cancerología, Mexico City, Mexico
| | - J F Sánchez-Ávila
- Escuela de Medicina y Ciencias de la Salud, Tecnológico de Monterrey, Monterrey, Nuevo León, Mexico
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30
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The role of RNA binding proteins in hepatocellular carcinoma. Adv Drug Deliv Rev 2022; 182:114114. [PMID: 35063534 DOI: 10.1016/j.addr.2022.114114] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2021] [Revised: 12/02/2021] [Accepted: 01/12/2022] [Indexed: 12/24/2022]
Abstract
Hepatocellular carcinoma (HCC) is one of the leading causes of overall cancer deaths worldwide with limited therapeutic options. Due to the heterogeneity of HCC pathogenesis, the molecular mechanisms underlying HCC development are not fully understood. Emerging evidence indicates that RNA-binding proteins (RBPs) play a vital role throughout hepatocarcinogenesis. Thus, a deeper understanding of how RBPs contribute to HCC progression will provide new tools for early diagnosis and prognosis of this devastating disease. In this review, we summarize the tumor suppressive and oncogenic roles of RBPs and their roles in hepatocarcinogenesis. The diagnostic and therapeutic potential of RBPs in HCC, including their limitations, are also discussed.
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31
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Riebensahm C, Chitundu H, Muula G, Chihota B, Sinkala E, Sunkutu V, Maurer MH, Dufour JF, Berzigotti A, Egger M, Bolton-Moore C, Vinikoor M, Wandeler G. Screening for hepatocellular carcinoma among adults with HIV/HBV co-infection in Zambia: a pilot study. Int J Infect Dis 2022; 116:391-396. [PMID: 34952210 PMCID: PMC9912380 DOI: 10.1016/j.ijid.2021.12.338] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2021] [Revised: 12/14/2021] [Accepted: 12/15/2021] [Indexed: 11/17/2022] Open
Abstract
BACKGROUND AND AIMS Chronic hepatitis B virus (HBV) infection is the main cause of hepatocellular carcinoma (HCC) in sub-Saharan Africa (SSA). An HCC screening initiative was piloted in an established cohort of individuals co-infected with human immunodeficiency virus (HIV) and HBV on antiretroviral therapy (ART) at two outpatient clinics in Lusaka, Zambia. METHODS All patients underwent abdominal ultrasound (AUS) and transient elastography. RESULTS Among 279 patients co-infected with HIV/HBV, 165 (59.1%) were men, median age was 34 years [interquartile range (IQR) 28-39 years] and median CD4 count was 246 cells/µL (IQR 112-355 cells/µL) at ART initiation. While 102 (55.7%) individuals had elevated transaminases, 114 (59.7%) had HBV levels >2000 IU/mL and 59 (24.6%) had significant fibrosis. At their first AUS measurement, 75 (26.9%) participants had hepatomegaly and 69 (24.7%) had periportal fibrosis. Five patients had a liver lesion >1 cm, an indication for confirmatory imaging. CONCLUSIONS In one of the first HCC screening initiatives in SSA, 2% of patients co-infected with HIV/HBV had significant liver lesions, and one-quarter had findings suggestive of schistosomiasis-induced liver damage.
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Affiliation(s)
- C Riebensahm
- Department of Infectious Diseases, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland.
| | - H Chitundu
- Department of Radiology, University Teaching Hospital, Lusaka, Zambia
| | - G Muula
- Centre for Infectious Diseases Research in Zambia, Lusaka, Zambia
| | - B Chihota
- Centre for Infectious Diseases Research in Zambia, Lusaka, Zambia; Institute of Social and Preventive Medicine, University of Bern, Bern, Switzerland
| | - E Sinkala
- Department of Medicine, University Teaching Hospital, Lusaka, Zambia
| | - V Sunkutu
- Department of Radiology, University Teaching Hospital, Lusaka, Zambia
| | - M H Maurer
- Department of Radiology, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
| | - J F Dufour
- Hepatology, Department of BioMedical Research, University of Bern, Bern, Switzerland
| | - A Berzigotti
- Department for Visceral Surgery and Medicine, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland; Hepatology, Department of BioMedical Research, University of Bern, Bern, Switzerland
| | - M Egger
- Institute of Social and Preventive Medicine, University of Bern, Bern, Switzerland; Centre for Infectious Diseases Research, University of Cape Town, Cape Town, Republic of South Africa
| | - C Bolton-Moore
- Centre for Infectious Diseases Research in Zambia, Lusaka, Zambia; Department of Medicine, University of Alabama, Birmingham, AL, USA
| | - M Vinikoor
- Centre for Infectious Diseases Research in Zambia, Lusaka, Zambia; Department of Medicine, University of Alabama, Birmingham, AL, USA
| | - G Wandeler
- Department of Infectious Diseases, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland; Institute of Social and Preventive Medicine, University of Bern, Bern, Switzerland
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32
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Ramezani M, Jalalian SH, Taghdisi SM, Abnous K, Alibolandi M. Optical and Electrochemical Aptasensors for Sensitive Detection of Aflatoxin B 1 and Aflatoxin M 1 in Blood Serum, Grape Juice, and Milk Samples. METHODS IN MOLECULAR BIOLOGY (CLIFTON, N.J.) 2022; 2393:417-436. [PMID: 34837191 DOI: 10.1007/978-1-0716-1803-5_21] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
Aflatoxin food contamination with toxic and carcinogenic impacts on human health is a global concern. We have developed aptasensors for the detection of Aflatoxin M1 (AFM1) and B1 (AFB1) using electrochemical and optical methods. In the first method, an electrochemical aptasensor was designed for the detection of AFM1 based on complementary strand of AFM1 aptamer that was attached onto the gold nanoparticles and a hairpin-shaped AFM1 aptamer. The designed electrochemical aptasensor showed high selectivity toward AFM1 with a limit of detection (LOD) as low as 0.9 nM. Moreover, the developed aptasensor was successfully used to detect AFM1 in milk and serum with LODs of 1.8 and 1.2 nM, respectively. In the second method, a novel electrochemical aptasensor was developed based on the π-shape structure of AFB1 aptamer. The detection limit was found to be 2 pg/mL in buffer. Also, the developed aptasensor was used to analyze AFB1 spiked human serum and grape juice samples, and the recoveries were 95.4-108.1%. In another method, a fluorescent sensing scheme was developed for AFB1 detection based on a hairpin structure of G-quadruplex oligonucleotide-aptamer chimera, streptavidin-coated silica nanoparticles (SNP-streptavidin) and N-methyl mesoporphyrin IX (NMM). The LOD was reported as 8 pg/mL with a linear range of 30-900 pg/mL. Moreover, the developed sensor could detect AFB1 in serum and grape juice with the LOD of 9.8 and 11.2 pg/mL, respectively.
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Affiliation(s)
- Mohammad Ramezani
- Pharmaceutical Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran.
- Department of Pharmaceutical Biotechnology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran.
| | - Seyed Hamid Jalalian
- Pharmaceutical Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran
- Students Research Committee, Department of Pharmaceutical Nanotechnology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
- Academic Center for Education, Culture and Research (ACECR)-Mashhad Branch, Mashhad, Iran
| | - Seyed Mohammad Taghdisi
- Targeted Drug Delivery Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Khalil Abnous
- Pharmaceutical Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran
- Department of Medicinal Chemistry, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Mona Alibolandi
- Pharmaceutical Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran
- Department of Pharmaceutical Biotechnology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
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Chen Y. Recent progress in fluorescent aptasensors for the detection of aflatoxin B1 in food. ANALYTICAL METHODS : ADVANCING METHODS AND APPLICATIONS 2022; 14:86-96. [PMID: 34897320 DOI: 10.1039/d1ay01714d] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/14/2023]
Abstract
Aflatoxin B1 pollution is one of the most critical issues of food safety and has been categorized as a group I carcinogen by the International Agency for Research on Cancer. Aflatoxin B1 exists in various foods and feedstuff products and can be produced and contaminate food products in all processes, including growth, harvest, storage, or processing. Therefore, it is of great value for detecting and on-site monitoring aflatoxin B1. Aptamers are short single-stranded DNA or RNA obtained from the nucleic acid molecular library through SELEX. With advantages of high specificity, large affinity, and easy modification, aptasensors have become popular in a wide range of promising applications. This review focuses on recent advances on fluorescent aptamer sensors for the detection of aflatoxin B1, including their design strategies, working mechanisms, and applications to on-site detection. Finally, the current challenges and prospects are discussed.
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Affiliation(s)
- Yi Chen
- Key Laboratory of Photochemical Conversion and Optoelectronic Materials, Technical Institute of Physics and Chemistry, Chinese Academy of Sciences, Beijing, 100190, China.
- University of Chinese Academy of Sciences, Beijing, 100049, China
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Gomez-Quiroz LE, Roman S. Influence of genetic and environmental risk factors in the development of hepatocellular carcinoma in Mexico. Ann Hepatol 2022; 27 Suppl 1:100649. [PMID: 34902602 DOI: 10.1016/j.aohep.2021.100649] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/08/2021] [Revised: 11/20/2021] [Accepted: 11/24/2021] [Indexed: 02/06/2023]
Abstract
The latest studies on the epidemiology of diverse types of cancers have located in the scene the relevance of liver tumors, particularly hepatocellular carcinoma (HCC). HCC is a life-threatening malignancy triggered by chronic exposure to hepatitis B and C viruses, excessive alcohol intake, hepatic lipid droplet accumulation, and aflatoxins that lead to persistent liver damage. The occurrence of such etiological risk factors deeply marks the variability in the incidence of HCC worldwide reflected by geography, ethnicity, age, and lifestyle factors influenced by cultural aspects. New perspectives on the primary risk factors and their potential gene-environment interactions (GxE) have been well-addressed in some cancers; however, it continues to be a partially characterized issue in liver malignancies. In this review, the epidemiology of the risk factors for HCC are described enhancing the GxE interactions identified in Mexico, which could mark the risk of this liver malignancy among the population and the measures needed to revert them. Updated healthcare policies focusing on preventive care should be tailored based on the genetic and environmental risk factors, which may influence the effect of the etiological agents of HCC. Robust regional investigations related to epidemiological, clinical, and basic studies are warranted to understand this health problem complying with the rules of ethnic, genetic, environmental, and social diversity.
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Affiliation(s)
- Luis E Gomez-Quiroz
- Área de Medicina Experimental y Traslacional, Departamento de Ciencias de la Salud, Universidad Autónoma Metropolitana-Iztapalapa, Mexico City, Mexico
| | - Sonia Roman
- Department of Genomic Medicine in Hepatology, Civil Hospital of Guadalajara, "Fray Antonio Alcalde," Guadalajara, Jalisco, Mexico; Health Sciences Center, University of Guadalajara, Guadalajara, Jalisco, Mexico.
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Kortei NK, Annan T, Kyei-Baffour V, Essuman EK, Boakye AA, Tettey CO, Boadi NO. Exposure assessment and cancer risk characterization of aflatoxin M1 (AFM1) through ingestion of raw cow milk in southern Ghana. Toxicol Rep 2022; 9:1189-1197. [DOI: 10.1016/j.toxrep.2022.05.015] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2021] [Revised: 05/16/2022] [Accepted: 05/17/2022] [Indexed: 12/27/2022] Open
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Beier JI, Arteel GE. Environmental exposure as a risk-modifying factor in liver diseases: Knowns and unknowns. Acta Pharm Sin B 2021; 11:3768-3778. [PMID: 35024305 PMCID: PMC8727918 DOI: 10.1016/j.apsb.2021.09.005] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2021] [Revised: 06/24/2021] [Accepted: 08/19/2021] [Indexed: 02/07/2023] Open
Abstract
Liver diseases are considered to predominantly possess an inherited or xenobiotic etiology. However, inheritance drives the ability to appropriately adapt to environmental stressors, and disease is the culmination of a maladaptive response. Thus “pure” genetic and “pure” xenobiotic liver diseases are modified by each other and other factors, identified or unknown. The purpose of this review is to highlight the knowledgebase of environmental exposure as a potential risk modifying agent for the development of liver disease by other causes. This exercise is not to argue that all liver diseases have an environmental component, but to challenge the assumption that the current state of our knowledge is sufficient in all cases to conclusively dismiss this as a possibility. This review also discusses key new tools and approaches that will likely be critical to address this question in the future. Taken together, identifying the key gaps in our understanding is critical for the field to move forward, or at the very least to “know what we don't know.”
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Affiliation(s)
- Juliane I. Beier
- Department of Medicine, Division of Gastroenterology, Hepatology and Nutrition, University of Pittsburgh, Pittsburgh, PA 15213, USA
- Pittsburgh Liver Research Center and University of Pittsburgh, Pittsburgh, PA 15213, USA
- Department of Environmental and Occupational Health, University of Pittsburgh, PA 15213, USA
- Corresponding authors.
| | - Gavin E. Arteel
- Department of Medicine, Division of Gastroenterology, Hepatology and Nutrition, University of Pittsburgh, Pittsburgh, PA 15213, USA
- Pittsburgh Liver Research Center and University of Pittsburgh, Pittsburgh, PA 15213, USA
- Corresponding authors.
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Liu H, Dong Z. Cancer Etiology and Prevention Principle: "1 + X". Cancer Res 2021; 81:5377-5395. [PMID: 34470778 DOI: 10.1158/0008-5472.can-21-1862] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2021] [Revised: 08/16/2021] [Accepted: 08/31/2021] [Indexed: 11/16/2022]
Abstract
Cancer was previously thought to be an inevitable aspect of human health with no effective treatments. However, the results of in-depth cancer research suggest that most types of cancer may be preventable. Therefore, a comprehensive understanding of the disparities in cancer burden caused by different risk factors is essential to inform and improve cancer prevention and control. Here, we propose the cancer etiology and prevention principle "1 + X," where 1 denotes the primary risk factor for a cancer and X represents the secondary contributing risk factors for the cancer. We elaborate upon the "1 + X" principle with respect to risk factors for several different cancer types. The "1 + X" principle can be used for precise prevention of cancer by eliminating the main cause of a cancer and minimizing the contributing factors at the same time.
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Affiliation(s)
- Hui Liu
- Department of Pathophysiology, School of Basic Medical Sciences, College of Medicine, Zhengzhou University, Zhengzhou, Henan, China
- China-US (Henan) Hormel Cancer Institute, Zhengzhou, Henan, China
| | - Zigang Dong
- Department of Pathophysiology, School of Basic Medical Sciences, College of Medicine, Zhengzhou University, Zhengzhou, Henan, China.
- China-US (Henan) Hormel Cancer Institute, Zhengzhou, Henan, China
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Kedar Mukthinuthalapati VVP, Sewram V, Ndlovu N, Kimani S, Abdelaziz AO, Chiao EY, Abou-Alfa GK. Hepatocellular Carcinoma in Sub-Saharan Africa. JCO Glob Oncol 2021; 7:756-766. [PMID: 34043413 PMCID: PMC8457845 DOI: 10.1200/go.20.00425] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
More than 80% of global hepatocellular carcinoma (HCC) patients are estimated to occur in sub-Saharan Africa (SSA) and Eastern Asia. The most common risk factor of HCC in SSA is chronic hepatitis B virus (HBV) infection, with the incidence highest in West Africa. HBV is highly endemic in SSA and is perpetuated by incomplete adherence to birth dose immunization, lack of longitudinal follow-up care, and impaired access to antiviral therapy. HBV may directly cause HCC through somatic genetic alterations or indirectly through altered liver function and liver cirrhosis. Other risk factors of HCC in SSA include aflatoxins and, to a lesser extent, African iron overload. HIV plus HBV co-infection increases the risk of developing HCC and is increasingly becoming more common because of improving the survival of patients with HIV infection. Compared with the rest of the world, patients with HCC in SSA have the lowest survival. This is partly due to the late presentation of HCC with advanced symptomatic disease as a result of underdeveloped surveillance practices. Moreover, access to care and resource limitations further limit outcomes for the patients who receive a diagnosis in SSA. There is a need for multipronged strategies to decrease the incidence of HCC and improve its outcomes in SSA.
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Affiliation(s)
| | - Vikash Sewram
- Department of Global Health, Faculty of Medicine and Health Sciences, African Cancer Institute, Stellenbosch University, Cape Town, South Africa
| | - Ntokozo Ndlovu
- University of Zimbabwe College of Health Sciences, Harare, Zimbabwe
| | - Stephen Kimani
- The University of North Carolina at Chapel Hill, Chapel Hill, NC
| | | | | | - Ghassan K Abou-Alfa
- Memorial Sloan Kettering Cancer Center, New York, NY.,Weill Medical College at Cornell University, New York, NY
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Awuchi CG, Ondari EN, Ogbonna CU, Upadhyay AK, Baran K, Okpala COR, Korzeniowska M, Guiné RPF. Mycotoxins Affecting Animals, Foods, Humans, and Plants: Types, Occurrence, Toxicities, Action Mechanisms, Prevention, and Detoxification Strategies-A Revisit. Foods 2021; 10:1279. [PMID: 34205122 PMCID: PMC8228748 DOI: 10.3390/foods10061279] [Citation(s) in RCA: 118] [Impact Index Per Article: 29.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2021] [Revised: 05/22/2021] [Accepted: 05/25/2021] [Indexed: 01/05/2023] Open
Abstract
Mycotoxins are produced by fungi and are known to be toxic to humans and animals. Common mycotoxins include aflatoxins, ochratoxins, zearalenone, patulin, sterigmatocystin, citrinin, ergot alkaloids, deoxynivalenol, fumonisins, trichothecenes, Alternaria toxins, tremorgenic mycotoxins, fusarins, 3-nitropropionic acid, cyclochlorotine, sporidesmin, etc. These mycotoxins can pose several health risks to both animals and humans, including death. As several mycotoxins simultaneously occur in nature, especially in foods and feeds, the detoxification and/or total removal of mycotoxins remains challenging. Moreover, given that the volume of scientific literature regarding mycotoxins is steadily on the rise, there is need for continuous synthesis of the body of knowledge. To supplement existing information, knowledge of mycotoxins affecting animals, foods, humans, and plants, with more focus on types, toxicity, and prevention measures, including strategies employed in detoxification and removal, were revisited in this work. Our synthesis revealed that mycotoxin decontamination, control, and detoxification strategies cut across pre-and post-harvest preventive measures. In particular, pre-harvest measures can include good agricultural practices, fertilization/irrigation, crop rotation, using resistant varieties of crops, avoiding insect damage, early harvesting, maintaining adequate humidity, and removing debris from the preceding harvests. On the other hand, post-harvest measures can include processing, chemical, biological, and physical measures. Additionally, chemical-based methods and other emerging strategies for mycotoxin detoxification can involve the usage of chitosan, ozone, nanoparticles, and plant extracts.
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Affiliation(s)
- Chinaza Godswill Awuchi
- Department of Biochemistry, Kampala International University, Bushenyi P.O. Box 20000, Uganda;
- School of Natural and Applied Sciences, Kampala International University, Kampala P.O. Box 20000, Uganda
| | - Erick Nyakundi Ondari
- Department of Biochemistry, Kampala International University, Bushenyi P.O. Box 20000, Uganda;
| | - Chukwuka U. Ogbonna
- Department of Biochemistry, Federal University of Agriculture Abeokuta, Abeokuta P.M.B. 2240, Ogun State, Nigeria;
| | - Anjani K. Upadhyay
- School of Biotechnology, KIIT University, Bhubaneswar 751019, Odisha, India;
| | - Katarzyna Baran
- Faculty of Biotechnology and Food Sciences, Wrocław University of Environmental and Life Sciences, 51-630 Wrocław, Poland; (K.B.); (M.K.)
| | - Charles Odilichukwu R. Okpala
- Faculty of Biotechnology and Food Sciences, Wrocław University of Environmental and Life Sciences, 51-630 Wrocław, Poland; (K.B.); (M.K.)
| | - Małgorzata Korzeniowska
- Faculty of Biotechnology and Food Sciences, Wrocław University of Environmental and Life Sciences, 51-630 Wrocław, Poland; (K.B.); (M.K.)
| | - Raquel P. F. Guiné
- CERNAS Research Centre, Polytechnic Institute of Viseu, 3504-510 Viseu, Portugal
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Pickova D, Ostry V, Toman J, Malir F. Aflatoxins: History, Significant Milestones, Recent Data on Their Toxicity and Ways to Mitigation. Toxins (Basel) 2021; 13:399. [PMID: 34205163 PMCID: PMC8227755 DOI: 10.3390/toxins13060399] [Citation(s) in RCA: 86] [Impact Index Per Article: 21.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2021] [Revised: 05/04/2021] [Accepted: 06/02/2021] [Indexed: 02/07/2023] Open
Abstract
In the early 1960s the discovery of aflatoxins began when a total of 100,000 turkey poults died by hitherto unknown turkey "X" disease in England. The disease was associated with Brazilian groundnut meal affected by Aspergillus flavus. The toxin was named Aspergillus flavus toxin-aflatoxin. From the point of view of agriculture, aflatoxins show the utmost importance. Until now, a total of 20 aflatoxins have been described, with B1, B2, G1, and G2 aflatoxins being the most significant. Contamination by aflatoxins is a global health problem. Aflatoxins pose acutely toxic, teratogenic, immunosuppressive, carcinogenic, and teratogenic effects. Besides food insecurity and human health, aflatoxins affect humanity at different levels, such as social, economical, and political. Great emphasis is placed on aflatoxin mitigation using biocontrol methods. Thus, this review is focused on aflatoxins in terms of historical development, the principal milestones of aflatoxin research, and recent data on their toxicity and different ways of mitigation.
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Affiliation(s)
- Darina Pickova
- Department of Biology, Faculty of Science, University of Hradec Kralove, Rokitanskeho 62, CZ-50003 Hradec Kralove, Czech Republic; (V.O.); (J.T.); (F.M.)
| | - Vladimir Ostry
- Department of Biology, Faculty of Science, University of Hradec Kralove, Rokitanskeho 62, CZ-50003 Hradec Kralove, Czech Republic; (V.O.); (J.T.); (F.M.)
- Center for Health, Nutrition and Food in Brno, National Institute of Public Health in Prague, Palackeho 3a, CZ-61242 Brno, Czech Republic
| | - Jakub Toman
- Department of Biology, Faculty of Science, University of Hradec Kralove, Rokitanskeho 62, CZ-50003 Hradec Kralove, Czech Republic; (V.O.); (J.T.); (F.M.)
| | - Frantisek Malir
- Department of Biology, Faculty of Science, University of Hradec Kralove, Rokitanskeho 62, CZ-50003 Hradec Kralove, Czech Republic; (V.O.); (J.T.); (F.M.)
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Péneau C, Zucman-Rossi J, Nault JC. Genomics of Viral Hepatitis-Associated Liver Tumors. J Clin Med 2021; 10:1827. [PMID: 33922394 PMCID: PMC8122827 DOI: 10.3390/jcm10091827] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2021] [Revised: 04/15/2021] [Accepted: 04/18/2021] [Indexed: 12/25/2022] Open
Abstract
Virus-related liver carcinogenesis is one of the main contributors of cancer-related death worldwide mainly due to the impact of chronic hepatitis B and C infections. Three mechanisms have been proposed to explain the oncogenic properties of hepatitis B virus (HBV) infection: induction of chronic inflammation and cirrhosis, expression of HBV oncogenic proteins, and insertional mutagenesis into the genome of infected hepatocytes. Hepatitis B insertional mutagenesis modifies the function of cancer driver genes and could promote chromosomal instability. In contrast, hepatitis C virus promotes hepatocellular carcinoma (HCC) occurrence mainly through cirrhosis development whereas the direct oncogenic role of the virus in human remains debated. Finally, adeno associated virus type 2 (AAV2), a defective DNA virus, has been associated with occurrence of HCC harboring insertional mutagenesis of the virus. Since these tumors developed in a non-cirrhotic context and in the absence of a known etiological factor, AAV2 appears to be the direct cause of tumor development in these patients via a mechanism of insertional mutagenesis altering similar oncogenes and tumor suppressor genes targeted by HBV. A better understanding of virus-related oncogenesis will be helpful to develop new preventive strategies and therapies directed against specific alterations observed in virus-related HCC.
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Affiliation(s)
- Camille Péneau
- Centre de Recherche des Cordeliers, Sorbonne Université, Inserm, Université de Paris, F-75006 Paris, France; (C.P.); (J.Z.-R.)
- Functional Genomics of Solid Tumors Laboratory, Équipe Labellisée Ligue Nationale Contre le Cancer, Labex OncoImmunology, F-75006 Paris, France
| | - Jessica Zucman-Rossi
- Centre de Recherche des Cordeliers, Sorbonne Université, Inserm, Université de Paris, F-75006 Paris, France; (C.P.); (J.Z.-R.)
- Functional Genomics of Solid Tumors Laboratory, Équipe Labellisée Ligue Nationale Contre le Cancer, Labex OncoImmunology, F-75006 Paris, France
- Hôpital Européen Georges Pompidou, APHP, F-75015 Paris, France
| | - Jean-Charles Nault
- Centre de Recherche des Cordeliers, Sorbonne Université, Inserm, Université de Paris, F-75006 Paris, France; (C.P.); (J.Z.-R.)
- Functional Genomics of Solid Tumors Laboratory, Équipe Labellisée Ligue Nationale Contre le Cancer, Labex OncoImmunology, F-75006 Paris, France
- Service d’hépatologie, Hôpital Avicenne, Hôpitaux Universitaires Paris-Seine-Saint-Denis, Assistance-Publique Hôpitaux de Paris, F-93000 Bobigny, France
- Unité de Formation et de Recherche Santé Médecine et Biologie Humaine, Université Paris Nord, F-93000 Bobigny, France
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Wokorach G, Landschoot S, Anena J, Audenaert K, Echodu R, Haesaert G. Mycotoxin profile of staple grains in northern Uganda: Understanding the level of human exposure and potential risks. Food Control 2021. [DOI: 10.1016/j.foodcont.2020.107813] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
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Ngo MHT, Jeng HY, Kuo YC, Nanda JD, Brahmadhi A, Ling TY, Chang TS, Huang YH. The Role of IGF/IGF-1R Signaling in Hepatocellular Carcinomas: Stemness-Related Properties and Drug Resistance. Int J Mol Sci 2021; 22:ijms22041931. [PMID: 33669204 PMCID: PMC7919800 DOI: 10.3390/ijms22041931] [Citation(s) in RCA: 51] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2021] [Revised: 02/10/2021] [Accepted: 02/10/2021] [Indexed: 12/12/2022] Open
Abstract
Insulin-like Growth Factor (IGF)/IGF-1 Receptor (IGF-1R) signaling is known to regulate stem cell pluripotency and differentiation to trigger cell proliferation, organ development, and tissue regeneration during embryonic development. Unbalanced IGF/IGF-1R signaling can promote cancer cell proliferation and activate cancer reprogramming in tumor tissues, especially in the liver. Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related death, with a high incidence and mortality rate in Asia. Most patients with advanced HCC develop tyrosine kinase inhibitor (TKI)-refractoriness after receiving TKI treatment. Dysregulation of IGF/IGF-1R signaling in HCC may activate expression of cancer stemness that leads to TKI refractoriness and tumor recurrence. In this review, we summarize the evidence for dysregulated IGF/IGF-1R signaling especially in hepatitis B virus (HBV)-associated HCC. The regulation of cancer stemness expression and drug resistance will be highlighted. Current clinical treatments and potential therapies targeting IGF/IGF-1R signaling for the treatment of HCC will be discussed.
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Affiliation(s)
- Mai-Huong Thi Ngo
- International PhD Program for Cell Therapy and Regeneration Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan; (M.-H.T.N.); (J.D.N.); (A.B.)
- Department of Biochemistry and Molecular Cell Biology, School of Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan
| | - Han-Yin Jeng
- Research Center of Cell Therapy and Regeneration Medicine, Taipei Medical University, Taipei 11031, Taiwan; (H.-Y.J.); (Y.-C.K.)
| | - Yung-Che Kuo
- Research Center of Cell Therapy and Regeneration Medicine, Taipei Medical University, Taipei 11031, Taiwan; (H.-Y.J.); (Y.-C.K.)
| | - Josephine Diony Nanda
- International PhD Program for Cell Therapy and Regeneration Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan; (M.-H.T.N.); (J.D.N.); (A.B.)
| | - Ageng Brahmadhi
- International PhD Program for Cell Therapy and Regeneration Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan; (M.-H.T.N.); (J.D.N.); (A.B.)
| | - Thai-Yen Ling
- Department and Graduate Institute of Pharmacology, National Taiwan University, Taipei 11031, Taiwan
- Correspondence: (T.-Y.L.); (T.-S.C.); (Y.-H.H.); Tel.: +886-2-2312-3456 (ext. 8-8322) (T.-Y.L.); +886-5-3621-000 (ext. 2242) (T.-S.C.); +886-2-2736-1661 (ext. 3150) (Y.-H.H.)
| | - Te-Sheng Chang
- School of Traditional Chinese Medicine, College of Medicine, Chang Gung University, Taoyuan 33382, Taiwan
- Division of Internal Medicine, Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Chiayi 61363, Taiwan
- Correspondence: (T.-Y.L.); (T.-S.C.); (Y.-H.H.); Tel.: +886-2-2312-3456 (ext. 8-8322) (T.-Y.L.); +886-5-3621-000 (ext. 2242) (T.-S.C.); +886-2-2736-1661 (ext. 3150) (Y.-H.H.)
| | - Yen-Hua Huang
- International PhD Program for Cell Therapy and Regeneration Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan; (M.-H.T.N.); (J.D.N.); (A.B.)
- Department of Biochemistry and Molecular Cell Biology, School of Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan
- Research Center of Cell Therapy and Regeneration Medicine, Taipei Medical University, Taipei 11031, Taiwan; (H.-Y.J.); (Y.-C.K.)
- Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan
- Center for Reproductive Medicine, Taipei Medical University Hospital, Taipei 11031, Taiwan
- Comprehensive Cancer Center, Taipei Medical University, Taipei 11031, Taiwan
- Research Center of Cancer Translational Medicine, Taipei Medical University, Taipei 11031, Taiwan
- PhD Program for Translational Medicine, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, Taiwan
- Correspondence: (T.-Y.L.); (T.-S.C.); (Y.-H.H.); Tel.: +886-2-2312-3456 (ext. 8-8322) (T.-Y.L.); +886-5-3621-000 (ext. 2242) (T.-S.C.); +886-2-2736-1661 (ext. 3150) (Y.-H.H.)
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Lim HC, Gordan JD. Tumor hepatitis B virus RNA identifies a clinically and molecularly distinct subset of hepatocellular carcinoma. PLoS Comput Biol 2021; 17:e1008699. [PMID: 33561166 PMCID: PMC7909678 DOI: 10.1371/journal.pcbi.1008699] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2020] [Revised: 02/26/2021] [Accepted: 01/13/2021] [Indexed: 12/24/2022] Open
Abstract
Hepatitis B virus (HBV) infection contributes to hepatocellular carcinoma (HCC) initiation and is associated with worse outcomes. Many prior studies of HBV-related HCC have not accounted for potential heterogeneity among HBV-related tumors by assessing whether HBV activity is present in tumor tissue. Here, we measured tumor HBV RNA, a proxy for viral activity, and investigated the association between HBV RNA status and several clinicogenomic characteristics. We obtained clinical, mutation, RNA-Seq and survival data for 439 HCC tumors from The Cancer Genome Atlas and International Cancer Genome Consortium. Tumors were classified as HBV RNA positive if they harbored >1 HBV RNA read per million human reads. We investigated the association between HBV RNA status and nonsynonymous somatic mutations, gene set expression, homologous recombination deficiency (HRD) score and mutation-specific survival. HBV RNA positive status was associated with higher nonsynonymous mutation rates of multiple genes, including TP53 and CDKN2A, while HBV RNA negative status was associated with higher nonsynonymous BAP1 mutation rate. HBV RNA positive status was also associated with increased transcription of genes involved in multiple DNA damage repair pathways, genes upregulated by MYC and mTORC1, and genes overexpressed in several HCC subclasses associated with a proliferative phenotype. Further, HBV RNA positive status was associated with increased three-biomarker HRD score (22.2 for HBV RNA+ vs. 16.0 for HBV RNA-). Finally, HBV RNA status was associated with multiple mutation-specific survival differences, including decreased survival for HBV RNA positive patients with nonsynonymous KEAP1 mutations compared to those without (hazard ratio 4.26). HCC tumors harboring genomic evidence of HBV activity therefore constitute a distinct HCC subset characterized by specific differences in nonsynonymous mutations, gene set expression, three-biomarker HRD score and mutation-specific survival. Hepatocellular carcinoma, the most common type of liver cancer, is the second leading cause of cancer death worldwide and is most commonly caused by hepatitis B virus infection. Currently, scientists have an incomplete understanding of the genomic basis of hepatocellular carcinoma associated with hepatitis B virus infection, because prior studies have been limited by imprecision in assessing hepatitis B virus infection status and heterogeneity in hepatitis B virus activity levels in liver tumors. This has limited scientists’ ability to devise new diagnostic and therapeutic options for hepatocellular carcinoma. In this study, we used computational genomics to directly measure hepatitis B virus RNA levels in a large dataset of hepatocellular carcinoma tumors, and found that tumors with measurable hepatitis B virus RNA levels are associated with a specific set of clinical and genomic characteristics. These characteristics have not previously been reported and harbor implications for future clinical and genomics research in hepatocellular carcinoma, as well as computational genomics efforts in other cancer types.
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Affiliation(s)
- Huat Chye Lim
- Division of Hematology and Oncology, University of California, San Francisco, San Francisco, California, United States of America
- * E-mail: (HCL); (JDG)
| | - John D. Gordan
- Division of Hematology and Oncology, University of California, San Francisco, San Francisco, California, United States of America
- * E-mail: (HCL); (JDG)
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45
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Hepatocellular carcinoma. Nat Rev Dis Primers 2021. [DOI: 10.1038/s41572-020-00240-3 order by 1-- #] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/11/2023]
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46
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Llovet JM, Kelley RK, Villanueva A, Singal AG, Pikarsky E, Roayaie S, Lencioni R, Koike K, Zucman-Rossi J, Finn RS. Hepatocellular carcinoma. Nat Rev Dis Primers 2021; 7:6. [PMID: 33479224 DOI: 10.1038/s41572-020-00240-3] [Citation(s) in RCA: 3691] [Impact Index Per Article: 922.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 12/08/2020] [Indexed: 02/07/2023]
Abstract
Liver cancer remains a global health challenge, with an estimated incidence of >1 million cases by 2025. Hepatocellular carcinoma (HCC) is the most common form of liver cancer and accounts for ~90% of cases. Infection by hepatitis B virus and hepatitis C virus are the main risk factors for HCC development, although non-alcoholic steatohepatitis associated with metabolic syndrome or diabetes mellitus is becoming a more frequent risk factor in the West. Moreover, non-alcoholic steatohepatitis-associated HCC has a unique molecular pathogenesis. Approximately 25% of all HCCs present with potentially actionable mutations, which are yet to be translated into the clinical practice. Diagnosis based upon non-invasive criteria is currently challenged by the need for molecular information that requires tissue or liquid biopsies. The current major advancements have impacted the management of patients with advanced HCC. Six systemic therapies have been approved based on phase III trials (atezolizumab plus bevacizumab, sorafenib, lenvatinib, regorafenib, cabozantinib and ramucirumab) and three additional therapies have obtained accelerated FDA approval owing to evidence of efficacy. New trials are exploring combination therapies, including checkpoint inhibitors and tyrosine kinase inhibitors or anti-VEGF therapies, or even combinations of two immunotherapy regimens. The outcomes of these trials are expected to change the landscape of HCC management at all evolutionary stages.
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Affiliation(s)
- Josep M Llovet
- Mount Sinai Liver Cancer Program, Division of Liver Diseases, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. .,Translational Research in Hepatic Oncology, Liver Unit, IDIBAPS, Hospital Clinic, University of Barcelona, Catalonia, Spain. .,Institució Catalana d'Estudis Avançats (ICREA), Barcelona, Catalonia, Spain.
| | - Robin Kate Kelley
- Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco (UCSF), San Francisco, CA, USA
| | - Augusto Villanueva
- Mount Sinai Liver Cancer Program, Division of Liver Diseases, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Amit G Singal
- Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, USA
| | - Eli Pikarsky
- The Lautenberg Center for Immunology and Cancer Research, IMRIC, The Hebrew University of Jerusalem, Jerusalem, Israel
| | - Sasan Roayaie
- White Plains Hospital Center for Cancer Care, Montefiore Health, White Plains, NY, USA
| | - Riccardo Lencioni
- Department of Radiology, Pisa University School of Medicine, Pisa, Italy.,Department of Radiology, Miami Cancer Insitute, Miami, FL, USA
| | - Kazuhiko Koike
- The University of Tokyo, Department of Gastroenterology, Tokyo, Japan
| | - Jessica Zucman-Rossi
- Centre de Recherche des Cordeliers, Sorbonne Université, Inserm, USPC, Université Paris Descartes, Université Paris Diderot, Paris, France.,Hôpital Européen Georges Pompidou, Assistance Publique-Hôpitaux de Paris, Paris, France
| | - Richard S Finn
- Department of Oncology, Geffen School of Medicine at UCLA, Los Angeles, CA, USA
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Hepatocellular carcinoma. Nat Rev Dis Primers 2021. [DOI: 10.1038/s41572-020-00240-3 and 1880=1880] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/11/2023]
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48
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Hepatocellular carcinoma. Nat Rev Dis Primers 2021. [DOI: 10.1038/s41572-020-00240-3 order by 1-- -] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/11/2023]
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49
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Hepatocellular carcinoma. Nat Rev Dis Primers 2021. [DOI: 10.1038/s41572-020-00240-3 order by 1-- gadu] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/11/2023]
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50
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Jiang L, Stärkel P, Fan JG, Fouts DE, Bacher P, Schnabl B. The gut mycobiome: a novel player in chronic liver diseases. J Gastroenterol 2021; 56:1-11. [PMID: 33151407 PMCID: PMC7819863 DOI: 10.1007/s00535-020-01740-5] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/27/2020] [Accepted: 10/15/2020] [Indexed: 02/07/2023]
Abstract
The human gut microbiome (bacteria, fungi, viruses, and archaea) is a complex and diverse ecosystem. It plays an important role in human health, but is involved in several intestinal and extraintestinal diseases. Most research to date has focused on the role of bacteria, while studies focusing on fungi (also referred to as "mycobiome" or "fungome") are still in its infancy. In this review, we focus on the existing literature available about the gut mycobiome with an emphasis on compositional mycobiome changes associated with liver diseases, the impact on pathogenesis of disease, and its potential use as therapeutic targets. We also provide insights into current methodologies of studying mycobiome, and we highlight the interkingdom interactions in the context of disease and how they affect health of the host. Herein, by focusing on the gut mycobiome, this review provides novel insights and directions for liver research.
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Affiliation(s)
- Lu Jiang
- Department of Medicine, University of California San Diego, MC0063, 9500 Gilman Drive, La Jolla, CA, 92093, USA
- Department of Medicine, VA San Diego Healthcare System, San Diego, CA, USA
| | - Peter Stärkel
- Cliniques Universitaires Saint Luc, Université Catholique de Louvain, Brussels, Belgium
| | - Jian-Gao Fan
- Department of Gastroenterology, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | | | - Petra Bacher
- Institute of Immunology, Christian-Albrechts-University of Kiel and UKSH Schleswig-Holstein, Kiel, Germany
- Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Kiel, Germany
| | - Bernd Schnabl
- Department of Medicine, University of California San Diego, MC0063, 9500 Gilman Drive, La Jolla, CA, 92093, USA.
- Department of Medicine, VA San Diego Healthcare System, San Diego, CA, USA.
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