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Yu X, Zhang Y, Luo F, Zhou Q, Zhu L. The role of microRNAs in the gastric cancer tumor microenvironment. Mol Cancer 2024; 23:170. [PMID: 39164671 PMCID: PMC11334576 DOI: 10.1186/s12943-024-02084-x] [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: 06/25/2024] [Accepted: 08/13/2024] [Indexed: 08/22/2024] Open
Abstract
BACKGROUND Gastric cancer (GC) is one of the deadliest malignant tumors with unknown pathogenesis. Due to its treatment resistance, high recurrence rate, and lack of reliable early detection techniques, a majority of patients have a poor prognosis. Therefore, identifying new tumor biomarkers and therapeutic targets is essential. This review aims to provide fresh insights into enhancing the prognosis of patients with GC by summarizing the processes through which microRNAs (miRNAs) regulate the tumor microenvironment (TME) and highlighting their critical role in the TME. MAIN TEXT A comprehensive literature review was conducted by focusing on the interactions among tumor cells, extracellular matrix, blood vessels, cancer-associated fibroblasts, and immune cells within the GC TME. The role of noncoding RNAs, known as miRNAs, in modulating the TME through various signaling pathways, cytokines, growth factors, and exosomes was specifically examined. Tumor formation, metastasis, and therapy in GC are significantly influenced by interactions within the TME. miRNAs regulate tumor progression by modulating these interactions through multiple signaling pathways, cytokines, growth factors, and exosomes. Dysregulation of miRNAs affects critical cellular processes such as cell proliferation, differentiation, angiogenesis, metastasis, and treatment resistance, contributing to the pathogenesis of GC. CONCLUSIONS miRNAs play a crucial role in the regulation of the GC TME, influencing tumor progression and patient prognosis. By understanding the mechanisms through which miRNAs control the TME, potential biomarkers and therapeutic targets can be identified to improve the prognosis of patients with GC.
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Affiliation(s)
- Xianzhe Yu
- Department of Medical Oncology, West China Hospital, Sichuan University, Sichuan Province, Cancer Center, Chengdu, 610041, People's Republic of China
- Lung Cancer Center/Lung Cancer Institute, West China Hospital, Sichuan University, Sichuan Province, Chengdu, 610041, People's Republic of China
- Department of Gastrointestinal Surgery, Chengdu Second People's Hospital, Sichuan Province, No. 10 Qinyun Nan Street, Chengdu, 610041, People's Republic of China
| | - Yin Zhang
- Department of Respiratory and Critical Care Medicine, West China Hospital, Sichuan University, Chengdu, 610041, China
- Laboratory of Pulmonary Immunology and Inflammation, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu, 610041, China
- Clinical Research Center for Respiratory Disease, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Fengming Luo
- Department of Respiratory and Critical Care Medicine, West China Hospital, Sichuan University, Chengdu, 610041, China.
- Laboratory of Pulmonary Immunology and Inflammation, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu, 610041, China.
- Clinical Research Center for Respiratory Disease, West China Hospital, Sichuan University, Chengdu, 610041, China.
| | - Qinghua Zhou
- Department of Medical Oncology, West China Hospital, Sichuan University, Sichuan Province, Cancer Center, Chengdu, 610041, People's Republic of China.
- Lung Cancer Center/Lung Cancer Institute, West China Hospital, Sichuan University, Sichuan Province, Chengdu, 610041, People's Republic of China.
| | - Lingling Zhu
- Department of Medical Oncology, West China Hospital, Sichuan University, Sichuan Province, Cancer Center, Chengdu, 610041, People's Republic of China.
- Lung Cancer Center/Lung Cancer Institute, West China Hospital, Sichuan University, Sichuan Province, Chengdu, 610041, People's Republic of China.
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Zhou J, Zhang M, Wang H, Zhong X, Yang X. Role of Helicobacter pylori virulence factors and alteration of the Tumor Immune Microenvironment: challenges and opportunities for Cancer Immunotherapy. Arch Microbiol 2024; 206:167. [PMID: 38485861 DOI: 10.1007/s00203-024-03908-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2024] [Revised: 02/19/2024] [Accepted: 02/22/2024] [Indexed: 03/19/2024]
Abstract
Various forms of malignancies have been linked to Helicobacter pylori. Despite advancements in chemotherapeutic and surgical approaches, the management of cancer, particularly at advanced stages, increasingly relies on the integration of immunotherapy. As a novel, safe therapeutic modality, immunotherapy harnesses the immune system of the patient to treat cancer, thereby broadening treatment options. However, there is evidence that H. pylori infection may influence the effectiveness of immunotherapy in various types of cancer. This association is related to H. pylori virulence factors and the tumor microenvironment. This review discusses the influence of H. pylori infection on immunotherapy in non-gastrointestinal and gastrointestinal tumors, the mechanisms underlying this relationship, and directions for the development of improved immunotherapy strategies.
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Affiliation(s)
- Junyi Zhou
- Department of Oncology, The Huai'an Clinical College of Xuzhou Medical University, Huai'an, Jiangsu, China
| | - Minna Zhang
- Department of Gastroenterology, The Affiliated Huai'an No. 1 People's Hospital of Nanjing Medical University, Huai'an, Jiangsu, China
| | - HongGang Wang
- Department of Gastroenterology, The Affiliated Huai'an No. 1 People's Hospital of Nanjing Medical University, Huai'an, Jiangsu, China
| | - Xiaomin Zhong
- Department of Oncology, The Huai'an Clinical College of Xuzhou Medical University, Huai'an, Jiangsu, China.
| | - XiaoZhong Yang
- Department of Gastroenterology, The Affiliated Huai'an No. 1 People's Hospital of Nanjing Medical University, Huai'an, Jiangsu, China.
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Lunger C, Shen Z, Holcombe H, Mannion AJ, Dzink-Fox J, Kurnick S, Feng Y, Muthupalani S, Carrasco SE, Wilson KT, Peek RM, Piazuelo MB, Morgan DR, Armijo AL, Mammoliti M, Wang TC, Fox JG. Gastric coinfection with thiopeptide-positive Cutibacterium acnes decreases FOXM1 and pro-inflammatory biomarker expression in a murine model of Helicobacter pylori-induced gastric cancer. Microbiol Spectr 2024; 12:e0345023. [PMID: 38014984 PMCID: PMC10783005 DOI: 10.1128/spectrum.03450-23] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2023] [Accepted: 10/19/2023] [Indexed: 11/29/2023] Open
Abstract
IMPORTANCE H. pylori infects half of the world population and is the leading cause of gastric cancer. We previously demonstrated that gastric cancer risk is associated with gastric microbiota. Specifically, gastric urease-positive Staphylococcus epidermidis and Streptococcus salivarius had contrasting effects on H. pylori-associated gastric pathology and immune responses in germ-free INS-GAS mice. As gastritis progresses to gastric cancer, the oncogenic transcription factor Foxm1 becomes increasingly expressed. In this study, we evaluated the gastric commensal C. acnes, certain strains of which produce thiopeptides that directly inhibit FOXM1. Thiopeptide-positive C. acnes was isolated from Nicaraguan patient gastric biopsies and inoculated into germ-free INS-GAS mice with H. pylori. We, therefore, asked whether coinfection with C. acnes expressing thiopeptide and H. pylori would decrease gastric Foxm1 expression and pro-inflammatory cytokine mRNA and protein levels. Our study supports the growing literature that specific non-H. pylori gastric bacteria affect inflammatory and cancer biomarkers in H. pylori pathogenesis.
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Affiliation(s)
- Courtney Lunger
- Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA
| | - Zeli Shen
- Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA
| | - Hilda Holcombe
- Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA
| | - Anthony J. Mannion
- Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA
| | - JoAnn Dzink-Fox
- Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA
| | - Susanna Kurnick
- Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA
| | - Yan Feng
- Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA
| | - Sureshkumar Muthupalani
- Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA
| | - Sebastian E. Carrasco
- Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA
| | - Keith T. Wilson
- Division of Gastroenterology, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Richard M. Peek
- Division of Gastroenterology, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - M. Blanca Piazuelo
- Division of Gastroenterology, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Douglas R. Morgan
- Division of Gastroenterology and Hepatology, Heersink School of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA
| | - Amanda L. Armijo
- Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA
| | - Melissa Mammoliti
- Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA
| | - Timothy C. Wang
- Division of Gastroenterology and Irvine Cancer Research Center, Columbia University, New York, New York, USA
| | - James G. Fox
- Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA
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Acquisition of paclitaxel resistance modulates the biological traits of gastric cancer AGS cells and facilitates epithelial to mesenchymal transition and angiogenesis. Naunyn Schmiedebergs Arch Pharmacol 2022; 395:515-533. [PMID: 35122114 DOI: 10.1007/s00210-022-02217-3] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2021] [Accepted: 01/31/2022] [Indexed: 12/12/2022]
Abstract
PURPOSE This study aims to develop a paclitaxel (PTX)-resistant gastric cancer AGS cells (AGS-R) and evaluate the mechanisms of drug resistance. METHODS AGS cells were successively treated with increasing PTX concentrations. Cross-resistance of established AGS-R, the molecular patterns of cell survival, evasion of apoptosis, epithelial-mesenchymal transition (EMT), and the angiogenic potential were evaluated. RESULTS AGS-R was induced within six months of PTX exposure. Extension of the treatment resulted in PTX-resistance beyond clinical levels. The established AGS-R showed resistance to vincristine and doxorubicin but not cisplatin. Upon induction of resistance, the expressions of MDR-1 (P < 0.001) and MRP-1 (P < 0.01) genes and proteins significantly increased. AGS-R cells had elevated levels of BCL-2, pro-CASP3, cleaved-NOTCH1, HES1, HEY1, NF-κB, PI3K, p-AKT, HIF-1α, Cyclin A, and B1 as compared with parental cells (at least P < 0.01). The protein levels of BAX, CASP3, P53, and P21 (at least P < 0.01) as well as intracellular ROS (P < 0.001) were reduced in AGS-R. A relative arrest at the G2/M phase (15.8 ± 0.75 vs. 26.7 ± 1.67) of the cell cycle and enrichment of AGS-R cells for CD44 marker (9 ± 0.6 vs. 1 ± 0.8) (P < 0.001) were detected by flow cytometry. While the E-cadherin expression was reduced (P < 0.001), the protein levels of Vimentin, N-cadherin, SLUG, and SNAIL were increased (at least P < 0.05). The angiogenic activity and release of VEGF and MMP2/9 were increased in AGS-R cells relative to the AGS line (P < 0.001). CONCLUSION AGS-R cells could bypass chemotherapy stress by expressing the genes coding for efflux pumps and altering some key signaling in favor of survival, EMT, and angiogenesis.
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Liu C, Barger CJ, Karpf AR. FOXM1: A Multifunctional Oncoprotein and Emerging Therapeutic Target in Ovarian Cancer. Cancers (Basel) 2021; 13:3065. [PMID: 34205406 PMCID: PMC8235333 DOI: 10.3390/cancers13123065] [Citation(s) in RCA: 36] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2021] [Revised: 06/11/2021] [Accepted: 06/16/2021] [Indexed: 02/08/2023] Open
Abstract
Forkhead box M1 (FOXM1) is a member of the conserved forkhead box (FOX) transcription factor family. Over the last two decades, FOXM1 has emerged as a multifunctional oncoprotein and a robust biomarker of poor prognosis in many human malignancies. In this review article, we address the current knowledge regarding the mechanisms of regulation and oncogenic functions of FOXM1, particularly in the context of ovarian cancer. FOXM1 and its associated oncogenic transcriptional signature are enriched in >85% of ovarian cancer cases and FOXM1 expression and activity can be enhanced by a plethora of genomic, transcriptional, post-transcriptional, and post-translational mechanisms. As a master transcriptional regulator, FOXM1 promotes critical oncogenic phenotypes in ovarian cancer, including: (1) cell proliferation, (2) invasion and metastasis, (3) chemotherapy resistance, (4) cancer stem cell (CSC) properties, (5) genomic instability, and (6) altered cellular metabolism. We additionally discuss the evidence for FOXM1 as a cancer biomarker, describe the rationale for FOXM1 as a cancer therapeutic target, and provide an overview of therapeutic strategies used to target FOXM1 for cancer treatment.
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Affiliation(s)
| | | | - Adam R. Karpf
- Eppley Institute and Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE 68918-6805, USA; (C.L.); (C.J.B.)
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6
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Wang C, Hu Y, Yang H, Wang S, Zhou B, Bao Y, Huang Y, Luo Q, Yang C, Xie X, Yang S. Function of Non-coding RNA in Helicobacter pylori-Infected Gastric Cancer. Front Mol Biosci 2021; 8:649105. [PMID: 34046430 PMCID: PMC8144459 DOI: 10.3389/fmolb.2021.649105] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2021] [Accepted: 03/10/2021] [Indexed: 12/12/2022] Open
Abstract
Gastric cancer is a common malignant tumor of the digestive system. Its occurrence and development are the result of a combination of genetic, environmental, and microbial factors. Helicobacter pylori infection is a chronic infection that is closely related to the occurrence of gastric tumorigenesis. Non-coding RNA has been demonstrated to play a very important role in the organism, exerting a prominent role in the carcinogenesis, proliferation, apoptosis, invasion, metastasis, and chemoresistance of tumor progression. H. pylori infection affects the expression of non-coding RNA at multiple levels such as genetic polymorphisms and signaling pathways, thereby promoting or inhibiting tumor progression or chemoresistance. This paper mainly introduces the relationship between H. pylori-infected gastric cancer and non-coding RNA, providing a new perspective for gastric cancer treatment.
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Affiliation(s)
- Chao Wang
- Department of Gastroenterology, Xinqiao Hospital, Third Military Medical University, Chongqing, China
| | - Yiyang Hu
- Department of Gastroenterology, Xinqiao Hospital, Third Military Medical University, Chongqing, China
| | - Huan Yang
- Department of Gastroenterology, Xinqiao Hospital, Third Military Medical University, Chongqing, China
| | - Sumin Wang
- Department of Gastroenterology, Xinqiao Hospital, Third Military Medical University, Chongqing, China
| | - Bo Zhou
- Department of Gastroenterology, Xinqiao Hospital, Third Military Medical University, Chongqing, China
| | - Yulu Bao
- Department of Gastroenterology, Xinqiao Hospital, Third Military Medical University, Chongqing, China
| | - Yu Huang
- Department of Gastroenterology, Xinqiao Hospital, Third Military Medical University, Chongqing, China
| | - Qiang Luo
- Department of Gastroenterology, Xinqiao Hospital, Third Military Medical University, Chongqing, China
| | - Chuan Yang
- Department of Gastroenterology, Xinqiao Hospital, Third Military Medical University, Chongqing, China
| | - Xia Xie
- Department of Gastroenterology, Xinqiao Hospital, Third Military Medical University, Chongqing, China
| | - Shiming Yang
- Department of Gastroenterology, Xinqiao Hospital, Third Military Medical University, Chongqing, China
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7
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Baj J, Forma A, Sitarz M, Portincasa P, Garruti G, Krasowska D, Maciejewski R. Helicobacter pylori Virulence Factors-Mechanisms of Bacterial Pathogenicity in the Gastric Microenvironment. Cells 2020; 10:27. [PMID: 33375694 PMCID: PMC7824444 DOI: 10.3390/cells10010027] [Citation(s) in RCA: 202] [Impact Index Per Article: 40.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2020] [Revised: 12/18/2020] [Accepted: 12/22/2020] [Indexed: 12/11/2022] Open
Abstract
Gastric cancer constitutes one of the most prevalent malignancies in both sexes; it is currently the fourth major cause of cancer-related deaths worldwide. The pathogenesis of gastric cancer is associated with the interaction between genetic and environmental factors, among which infection by Helicobacter pylori (H. pylori) is of major importance. The invasion, survival, colonization, and stimulation of further inflammation within the gastric mucosa are possible due to several evasive mechanisms induced by the virulence factors that are expressed by the bacterium. The knowledge concerning the mechanisms of H. pylori pathogenicity is crucial to ameliorate eradication strategies preventing the possible induction of carcinogenesis. This review highlights the current state of knowledge and the most recent findings regarding H. pylori virulence factors and their relationship with gastric premalignant lesions and further carcinogenesis.
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Affiliation(s)
- Jacek Baj
- Department of Anatomy, Medical University of Lublin, 20-400 Lublin, Poland;
| | - Alicja Forma
- Chair and Department of Forensic Medicine, Medical University of Lublin, 20-090 Lublin, Poland;
| | - Monika Sitarz
- Department of Conservative Dentistry with Endodontics, Medical University of Lublin, 20-090 Lublin, Poland;
| | - Piero Portincasa
- Clinica Medica “Augusto Murri”, Department of Biomedical Sciences and Human Oncology, University of Bari “Aldo Moro”, 70124 Bari, Italy;
| | - Gabriella Garruti
- Section of Endocrinology, Department of Emergency and Organ Transplantations, University of Bari “Aldo Moro” Medical School, Piazza G. Cesare 11, 70124 Bari, Italy;
| | - Danuta Krasowska
- Department of Dermatology, Venerology and Paediatric Dermatology of Medical University of Lublin, 20-081 Lublin, Poland;
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Baj J, Korona-Głowniak I, Forma A, Maani A, Sitarz E, Rahnama-Hezavah M, Radzikowska E, Portincasa P. Mechanisms of the Epithelial-Mesenchymal Transition and Tumor Microenvironment in Helicobacter pylori-Induced Gastric Cancer. Cells 2020; 9:1055. [PMID: 32340207 PMCID: PMC7225971 DOI: 10.3390/cells9041055] [Citation(s) in RCA: 105] [Impact Index Per Article: 21.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2020] [Revised: 04/16/2020] [Accepted: 04/17/2020] [Indexed: 12/11/2022] Open
Abstract
Helicobacter pylori (H. pylori) is one of the most common human pathogens, affecting half of the world's population. Approximately 20% of the infected patients develop gastric ulcers or neoplastic changes in the gastric stroma. An infection also leads to the progression of epithelial-mesenchymal transition within gastric tissue, increasing the probability of gastric cancer development. This paper aims to review the role of H. pylori and its virulence factors in epithelial-mesenchymal transition associated with malignant transformation within the gastric stroma. The reviewed factors included: CagA (cytotoxin-associated gene A) along with induction of cancer stem-cell properties and interaction with YAP (Yes-associated protein pathway), tumor necrosis factor α-inducing protein, Lpp20 lipoprotein, Afadin protein, penicillin-binding protein 1A, microRNA-29a-3p, programmed cell death protein 4, lysosomal-associated protein transmembrane 4β, cancer-associated fibroblasts, heparin-binding epidermal growth factor (HB-EGF), matrix metalloproteinase-7 (MMP-7), and cancer stem cells (CSCs). The review summarizes the most recent findings, providing insight into potential molecular targets and new treatment strategies for gastric cancer.
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Affiliation(s)
- Jacek Baj
- Chair and Department of Anatomy, Medical University of Lublin, 20-090 Lublin, Poland;
| | - Izabela Korona-Głowniak
- Department of Pharmaceutical Microbiology with Laboratory for Microbiological Diagnostics, Medical University of Lublin, Chodzki 1 Street, 20-093 Lublin, Poland;
| | - Alicja Forma
- Chair and Department of Forensic Medicine, Medical University of Lublin, 20-090 Lublin, Poland;
| | - Amr Maani
- Chair and Department of Anatomy, Medical University of Lublin, 20-090 Lublin, Poland;
| | - Elżbieta Sitarz
- Chair and 1st Department of Psychiatry, Psychotherapy and Early Intervention, Medical University of Lublin, Gluska Street 1, 20-439 Lublin, Poland;
| | - Mansur Rahnama-Hezavah
- Chair and Department of Oral Surgery, Medical University of Lublin, 20-081 Lublin, Poland;
| | - Elżbieta Radzikowska
- Department of Plastic Surgery, Central Clinical Hospital of the MSWiA in Warsaw, 01-211 Warsaw, Poland;
| | - Piero Portincasa
- Clinica Medica A. Murri, Department of Biomedical Sciences and Human Oncology, University of Bari Aldo Moro Medical School, 70126 Bari, Italy;
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