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Hayat A, Carter EP, King HW, Ors A, Doe A, Teijeiro SA, Charrot S, Godinho S, Cutillas P, Mohammed H, Grose RP, Ficz G. Low HER2 expression in normal breast epithelium enables dedifferentiation and malignant transformation via chromatin opening. Dis Model Mech 2023; 16:dmm049894. [PMID: 36661191 PMCID: PMC9922733 DOI: 10.1242/dmm.049894] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2022] [Accepted: 01/06/2023] [Indexed: 01/21/2023] Open
Abstract
Overexpression of the HER2 protein in breast cancer patients is a predictor of poor prognosis and resistance to therapies. We used an inducible breast cancer transformation system that allows investigation of early molecular changes. HER2 overexpression to similar levels as those observed in a subtype of HER2-positive breast cancer patients induced transformation of MCF10A cells and resulted in gross morphological changes, increased anchorage-independent growth of cells, and altered the transcriptional programme of genes associated with oncogenic transformation. Global phosphoproteomic analysis during HER2 induction predominantly detected an increase in protein phosphorylation. Intriguingly, this correlated with chromatin opening, as measured by ATAC-seq on acini isolated from 3D cell culture. HER2 overexpression resulted in opening of many distal regulatory regions and promoted reprogramming-associated heterogeneity. We found that a subset of cells acquired a dedifferentiated breast stem-like phenotype, making them likely candidates for malignant transformation. Our data show that this population of cells, which counterintuitively enriches for relatively low HER2 protein abundance and increased chromatin accessibility, possesses transformational drive, resulting in increased anchorage-independent growth in vitro compared to cells not displaying a stem-like phenotype.
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Affiliation(s)
- Ateequllah Hayat
- Institute of Medical and Biomedical Education, St George’s, University of London, Cranmer Terrace, Tooting, London SW17 0RE, UK
- Centre for Haemato-Oncology, Barts Cancer Institute, Queen Mary University of London, London EC1M 6BQ, UK
| | - Edward P. Carter
- Centre for Tumour Biology, Barts Cancer Institute, Queen Mary University of London, London EC1M 6BQ, UK
| | - Hamish W. King
- Epigenetics and Development Division, Walter and Eliza Hall Institute of Medical Research, Royal Parade, Parkville, VIC 3052, Australia
| | - Aysegul Ors
- Knight Cancer Institute, Oregon Health and Science University, 3181 S.W. Sam Jackson Park Road, Portland, OR 97239-3098, USA
| | - Aaron Doe
- Knight Cancer Institute, Oregon Health and Science University, 3181 S.W. Sam Jackson Park Road, Portland, OR 97239-3098, USA
| | - Saul A. Teijeiro
- Centre for Haemato-Oncology, Barts Cancer Institute, Queen Mary University of London, London EC1M 6BQ, UK
| | - Sarah Charrot
- Centre for Haemato-Oncology, Barts Cancer Institute, Queen Mary University of London, London EC1M 6BQ, UK
| | - Susana Godinho
- Centre for Molecular Oncology, Barts Cancer Institute, Queen Mary University of London, London EC1M 6BQ, UK
| | - Pedro Cutillas
- Centre for Haemato-Oncology, Barts Cancer Institute, Queen Mary University of London, London EC1M 6BQ, UK
| | - Hisham Mohammed
- Knight Cancer Institute, Oregon Health and Science University, 3181 S.W. Sam Jackson Park Road, Portland, OR 97239-3098, USA
| | - Richard P. Grose
- Centre for Tumour Biology, Barts Cancer Institute, Queen Mary University of London, London EC1M 6BQ, UK
| | - Gabriella Ficz
- Centre for Haemato-Oncology, Barts Cancer Institute, Queen Mary University of London, London EC1M 6BQ, UK
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4
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Song X, Hu Y, Li Y, Shao R, Liu F, Liu Y. Overview of current targeted therapy in gallbladder cancer. Signal Transduct Target Ther 2020; 5:230. [PMID: 33028805 PMCID: PMC7542154 DOI: 10.1038/s41392-020-00324-2] [Citation(s) in RCA: 90] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2020] [Revised: 08/08/2020] [Accepted: 09/10/2020] [Indexed: 02/08/2023] Open
Abstract
Gallbladder cancer (GBC) is rare, but is the most malignant type of biliary tract tumor. Unfortunately, only a small population of cancer patients is acceptable for the surgical resection, the current effective regimen; thus, the high mortality rate has been static for decades. To substantially circumvent the stagnant scenario, a number of therapeutic approaches owing to the creation of advanced technologic measures (e.g., next-generation sequencing, transcriptomics, proteomics) have been intensively innovated, which include targeted therapy, immunotherapy, and nanoparticle-based delivery systems. In the current review, we primarily focus on the targeted therapy capable of specifically inhibiting individual key molecules that govern aberrant signaling cascades in GBC. Global clinical trials of targeted therapy in GBC are updated and may offer great value for novel pathologic and therapeutic insights of this deadly disease, ultimately improving the efficacy of treatment.
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Affiliation(s)
- Xiaoling Song
- Department of General Surgery and Laboratory of General Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 1665 Kongjiang Road, 200092, Shanghai, China
- Shanghai Key Laboratory of Biliary Tract Disease Research, 1665 Kongjiang Road, 200092, Shanghai, China
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, School of Medicine, Shanghai Jiao Tong University, 200127, Shanghai, China
| | - Yunping Hu
- Department of General Surgery and Laboratory of General Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 1665 Kongjiang Road, 200092, Shanghai, China
- Shanghai Key Laboratory of Biliary Tract Disease Research, 1665 Kongjiang Road, 200092, Shanghai, China
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, School of Medicine, Shanghai Jiao Tong University, 200127, Shanghai, China
| | - Yongsheng Li
- Shanghai Key Laboratory of Biliary Tract Disease Research, 1665 Kongjiang Road, 200092, Shanghai, China
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, School of Medicine, Shanghai Jiao Tong University, 200127, Shanghai, China
- Department of Biliary-Pancreatic Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, 200127, Shanghai, China
| | - Rong Shao
- Shanghai Key Laboratory of Biliary Tract Disease Research, 1665 Kongjiang Road, 200092, Shanghai, China.
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, School of Medicine, Shanghai Jiao Tong University, 200127, Shanghai, China.
- Department of Pharmacology, Shanghai Jiao Tong University School of Medicine, 200025, Shanghai, China.
| | - Fatao Liu
- Department of General Surgery and Laboratory of General Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 1665 Kongjiang Road, 200092, Shanghai, China.
- Shanghai Key Laboratory of Biliary Tract Disease Research, 1665 Kongjiang Road, 200092, Shanghai, China.
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, School of Medicine, Shanghai Jiao Tong University, 200127, Shanghai, China.
| | - Yingbin Liu
- Shanghai Key Laboratory of Biliary Tract Disease Research, 1665 Kongjiang Road, 200092, Shanghai, China.
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, School of Medicine, Shanghai Jiao Tong University, 200127, Shanghai, China.
- Department of Biliary-Pancreatic Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, 200127, Shanghai, China.
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6
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Li G, Wu X, Qian W, Cai H, Sun X, Zhang W, Tan S, Wu Z, Qian P, Ding K, Lu X, Zhang X, Yan H, Song H, Guang S, Wu Q, Lobie PE, Shan G, Zhu T. CCAR1 5' UTR as a natural miRancer of miR-1254 overrides tamoxifen resistance. Cell Res 2016; 26:655-73. [PMID: 27002217 PMCID: PMC4897177 DOI: 10.1038/cr.2016.32] [Citation(s) in RCA: 55] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2016] [Revised: 02/03/2016] [Accepted: 02/03/2016] [Indexed: 01/05/2023] Open
Abstract
MicroRNAs (miRNAs) typically bind to unstructured miRNA-binding sites in target RNAs, leading to a mutual repression of expression. Here, we report that miR-1254 interacts with structured elements in cell cycle and apoptosis regulator 1 (CCAR1) 5′ untranslated region (UTR) and this interaction enhances the stability of both molecules. miR-1254 can also act as a repressor when binding to unstructured sites in its targets. Interestingly, structured miR-1254-targeting sites act as both a functional RNA motif-sensing unit, and an independent RNA functional unit that enhances miR-1254 expression. Artificially designed miRNA enhancers, termed “miRancers”, can stabilize and enhance the activity of miRNAs of interest. We further demonstrate that CCAR1 5′ UTR as a natural miRancer of endogenous miR-1254 re-sensitizes tamoxifen-resistant breast cancer cells to tamoxifen. Thus, our study presents a novel model of miRNA function, wherein highly structured miRancer-like motif-containing RNA fragments or miRancer molecules specifically interact with miRNAs, leading to reciprocal stabilization.
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Affiliation(s)
- Gaopeng Li
- The CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences, University of Science and Technology of China, Hefei, Anhui 230027, China
| | - Xiaoli Wu
- The CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences, University of Science and Technology of China, Hefei, Anhui 230027, China
| | - Wenchang Qian
- The CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences, University of Science and Technology of China, Hefei, Anhui 230027, China.,Hefei National Laboratory for Physical Sciences at Microscale, Hefei, Anhui 230027, China
| | - Huayong Cai
- The CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences, University of Science and Technology of China, Hefei, Anhui 230027, China
| | - Xinbao Sun
- The CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences, University of Science and Technology of China, Hefei, Anhui 230027, China
| | - Weijie Zhang
- The CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences, University of Science and Technology of China, Hefei, Anhui 230027, China.,Hefei National Laboratory for Physical Sciences at Microscale, Hefei, Anhui 230027, China
| | - Sheng Tan
- The CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences, University of Science and Technology of China, Hefei, Anhui 230027, China.,Hefei National Laboratory for Physical Sciences at Microscale, Hefei, Anhui 230027, China
| | - Zhengsheng Wu
- Department of Pathology, Anhui Medical University, Hefei, Anhui 230027, China
| | - Pengxu Qian
- Stowers Institute for Medical Research, Kansas City, Missouri 64110, USA
| | - Keshuo Ding
- Department of Pathology, Anhui Medical University, Hefei, Anhui 230027, China
| | - Xuefei Lu
- The CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences, University of Science and Technology of China, Hefei, Anhui 230027, China.,Hefei National Laboratory for Physical Sciences at Microscale, Hefei, Anhui 230027, China
| | - Xiao Zhang
- The CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences, University of Science and Technology of China, Hefei, Anhui 230027, China
| | - Hong Yan
- Department of Pathology, Anhui Medical University, Hefei, Anhui 230027, China
| | - Haifeng Song
- Department of Pharmacology and Toxicology, Beijing Institute of Radiation Medicine, Beijing 100850, China
| | - Shouhong Guang
- The CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences, University of Science and Technology of China, Hefei, Anhui 230027, China.,Hefei National Laboratory for Physical Sciences at Microscale, Hefei, Anhui 230027, China
| | - Qingfa Wu
- The CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences, University of Science and Technology of China, Hefei, Anhui 230027, China.,Hefei National Laboratory for Physical Sciences at Microscale, Hefei, Anhui 230027, China
| | - Peter E Lobie
- Cancer Science Institute of Singapore and Department of Pharmacology, National University of Singapore, Singapore 117599, Singapore
| | - Ge Shan
- The CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences, University of Science and Technology of China, Hefei, Anhui 230027, China.,Hefei National Laboratory for Physical Sciences at Microscale, Hefei, Anhui 230027, China
| | - Tao Zhu
- The CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences, University of Science and Technology of China, Hefei, Anhui 230027, China.,Hefei National Laboratory for Physical Sciences at Microscale, Hefei, Anhui 230027, China
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8
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Narayanan KB, Ali M, Barclay BJ, Cheng QS, D'Abronzo L, Dornetshuber-Fleiss R, Ghosh PM, Gonzalez Guzman MJ, Lee TJ, Leung PS, Li L, Luanpitpong S, Ratovitski E, Rojanasakul Y, Romano MF, Romano S, Sinha RK, Yedjou C, Al-Mulla F, Al-Temaimi R, Amedei A, Brown DG, Ryan EP, Colacci A, Hamid RA, Mondello C, Raju J, Salem HK, Woodrick J, Scovassi AI, Singh N, Vaccari M, Roy R, Forte S, Memeo L, Kim SY, Bisson WH, Lowe L, Park HH. Disruptive environmental chemicals and cellular mechanisms that confer resistance to cell death. Carcinogenesis 2015; 36 Suppl 1:S89-110. [PMID: 26106145 DOI: 10.1093/carcin/bgv032] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Cell death is a process of dying within biological cells that are ceasing to function. This process is essential in regulating organism development, tissue homeostasis, and to eliminate cells in the body that are irreparably damaged. In general, dysfunction in normal cellular death is tightly linked to cancer progression. Specifically, the up-regulation of pro-survival factors, including oncogenic factors and antiapoptotic signaling pathways, and the down-regulation of pro-apoptotic factors, including tumor suppressive factors, confers resistance to cell death in tumor cells, which supports the emergence of a fully immortalized cellular phenotype. This review considers the potential relevance of ubiquitous environmental chemical exposures that have been shown to disrupt key pathways and mechanisms associated with this sort of dysfunction. Specifically, bisphenol A, chlorothalonil, dibutyl phthalate, dichlorvos, lindane, linuron, methoxychlor and oxyfluorfen are discussed as prototypical chemical disruptors; as their effects relate to resistance to cell death, as constituents within environmental mixtures and as potential contributors to environmental carcinogenesis.
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Affiliation(s)
- Kannan Badri Narayanan
- Department of Chemistry and Biochemistry, Yeungnam University, Gyeongsan 712-749, South Korea, Sultan Zainal Abidin University, Malaysia, Plant Biotechnologies Inc, St. Albert AB, Canada, Computer Science Department, Southern Illinois University, Carbondale, IL 62901, USA, Department of Urology, University of California Davis, Sacramento, CA 95817, USA, Department of Pharmacology and Toxicology, University of Vienna, Austria, University of Puerto Rico, Medical Sciences Campus, School of Public Health, Nutrition Program, San Juan Puerto Rico 00936-5067, USA, Department of Anatomy, College of Medicine, Yeungnam University, Daegu, 705-717, South Korea, School of Biomedical Science, The Chinese University Of Hong Kong, Hong Kong, China, Siriraj Center of Excellence for Stem Cell Research, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand, Department of Otolaryngology/Head and Neck Surgery, Head and Neck Cancer Research Division, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA, Department of Pharmaceutical Sciences, Mary Babb Randolph Cancer Center, West Virginia University, Morgantown, WV 26506, USA, Department of Molecular Medicine and Medical Biotechnology, Federico II University of Naples, 80131 Naples, Italy, Department of Molecular and Experimental Medicine, MEM 180, The Scripps Research Institute, La Jolla, CA 92037, USA, Department of Biology, Jackson State University, Jackson, MS 39217, USA, Department of Pathology, Kuwait University, Safat 13110, Kuwait, Department of Experimental and Clinical Medicine, University of Firenze, Firenze, 50134, Italy, Department of Environmental and Radiological Health Sciences, Colorado state University/ Colorado School of Public Health, Fort Collins, CO 80523-1680, USA, Center for Environmental Carcinogenesis and Risk Assessment, Environmental Protection and Health Prevention Agency, Bologna, 40126, Italy, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, Se
| | - Manaf Ali
- Sultan Zainal Abidin University, Malaysia
| | | | - Qiang Shawn Cheng
- Computer Science Department, Southern Illinois University, Carbondale, IL 62901, USA
| | - Leandro D'Abronzo
- Department of Urology, University of California Davis, Sacramento, CA 95817, USA
| | | | - Paramita M Ghosh
- Department of Urology, University of California Davis, Sacramento, CA 95817, USA
| | - Michael J Gonzalez Guzman
- University of Puerto Rico, Medical Sciences Campus, School of Public Health, Nutrition Program, San Juan Puerto Rico 00936-5067, USA
| | - Tae-Jin Lee
- Department of Anatomy, College of Medicine, Yeungnam University, Daegu, 705-717, South Korea
| | - Po Sing Leung
- School of Biomedical Science, The Chinese University Of Hong Kong, Hong Kong, China
| | - Lin Li
- School of Biomedical Science, The Chinese University Of Hong Kong, Hong Kong, China
| | - Suidjit Luanpitpong
- Siriraj Center of Excellence for Stem Cell Research, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand
| | - Edward Ratovitski
- Department of Otolaryngology/Head and Neck Surgery, Head and Neck Cancer Research Division, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA
| | - Yon Rojanasakul
- Department of Pharmaceutical Sciences, Mary Babb Randolph Cancer Center, West Virginia University, Morgantown, WV 26506, USA
| | - Maria Fiammetta Romano
- Department of Molecular Medicine and Medical Biotechnology, Federico II University of Naples, 80131 Naples, Italy
| | - Simona Romano
- Department of Molecular Medicine and Medical Biotechnology, Federico II University of Naples, 80131 Naples, Italy
| | - Ranjeet K Sinha
- Department of Molecular and Experimental Medicine, MEM 180, The Scripps Research Institute, La Jolla, CA 92037, USA
| | - Clement Yedjou
- Department of Biology, Jackson State University, Jackson, MS 39217, USA
| | - Fahd Al-Mulla
- Department of Pathology, Kuwait University, Safat 13110, Kuwait
| | | | - Amedeo Amedei
- Department of Experimental and Clinical Medicine, University of Firenze, Firenze, 50134, Italy
| | - Dustin G Brown
- Department of Environmental and Radiological Health Sciences, Colorado state University/ Colorado School of Public Health, Fort Collins, CO 80523-1680, USA
| | - Elizabeth P Ryan
- Department of Environmental and Radiological Health Sciences, Colorado state University/ Colorado School of Public Health, Fort Collins, CO 80523-1680, USA
| | - Annamaria Colacci
- Center for Environmental Carcinogenesis and Risk Assessment, Environmental Protection and Health Prevention Agency, Bologna, 40126, Italy
| | - Roslida A Hamid
- Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, Serdang, Selangor 43400, Malaysia
| | - Chiara Mondello
- Institute of Molecular Genetics, National Research Council, Pavia, 27100, Italy
| | - Jayadev Raju
- Toxicology Research Division, Bureau of Chemical Safety Food Directorate, Health Products and Food Branch Health Canada, Ottawa, Ontario, K1A0K9, Canada
| | - Hosni K Salem
- Urology Department, Kasr Al-Ainy School of Medicine, Cairo University, El Manial, Cairo, 12515, Egypt
| | - Jordan Woodrick
- Molecular Oncology Program, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington DC, 20057, USA
| | - A Ivana Scovassi
- Institute of Molecular Genetics, National Research Council, Pavia, 27100, Italy
| | - Neetu Singh
- Advenced Molecular Science Research Centre, King George's Medical University, Lucknow, Uttar Pradesh, 226003, India
| | - Monica Vaccari
- Center for Environmental Carcinogenesis and Risk Assessment, Environmental Protection and Health Prevention Agency, Bologna, 40126, Italy
| | - Rabindra Roy
- Molecular Oncology Program, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington DC, 20057, USA
| | - Stefano Forte
- Mediterranean Institute of Oncology, Viagrande, 95029, Italy
| | - Lorenzo Memeo
- Mediterranean Institute of Oncology, Viagrande, 95029, Italy
| | - Seo Yun Kim
- Department of Internal Medicine, Korea Cancer Center Hospital, Seoul 139-706, South Korea
| | - William H Bisson
- Environmental and Molecular Toxicology, Environmental Health Science Center, Oregon State University, Corvallis, OR 97331, USA and
| | - Leroy Lowe
- Getting to Know Cancer, Truro, Nova Scotia, Canada
| | - Hyun Ho Park
- Department of Chemistry and Biochemistry, Yeungnam University, Gyeongsan 712-749, South Korea, Sultan Zainal Abidin University, Malaysia, Plant Biotechnologies Inc, St. Albert AB, Canada, Computer Science Department, Southern Illinois University, Carbondale, IL 62901, USA, Department of Urology, University of California Davis, Sacramento, CA 95817, USA, Department of Pharmacology and Toxicology, University of Vienna, Austria, University of Puerto Rico, Medical Sciences Campus, School of Public Health, Nutrition Program, San Juan Puerto Rico 00936-5067, USA, Department of Anatomy, College of Medicine, Yeungnam University, Daegu, 705-717, South Korea, School of Biomedical Science, The Chinese University Of Hong Kong, Hong Kong, China, Siriraj Center of Excellence for Stem Cell Research, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand, Department of Otolaryngology/Head and Neck Surgery, Head and Neck Cancer Research Division, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA, Department of Pharmaceutical Sciences, Mary Babb Randolph Cancer Center, West Virginia University, Morgantown, WV 26506, USA, Department of Molecular Medicine and Medical Biotechnology, Federico II University of Naples, 80131 Naples, Italy, Department of Molecular and Experimental Medicine, MEM 180, The Scripps Research Institute, La Jolla, CA 92037, USA, Department of Biology, Jackson State University, Jackson, MS 39217, USA, Department of Pathology, Kuwait University, Safat 13110, Kuwait, Department of Experimental and Clinical Medicine, University of Firenze, Firenze, 50134, Italy, Department of Environmental and Radiological Health Sciences, Colorado state University/ Colorado School of Public Health, Fort Collins, CO 80523-1680, USA, Center for Environmental Carcinogenesis and Risk Assessment, Environmental Protection and Health Prevention Agency, Bologna, 40126, Italy, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, Se
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