1
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Principe G, Lezcano V, Tiburzi S, Miravalles AB, García BN, Gumilar F, González-Pardo V. In vitro and in vivo evidence of the antineoplastic activity of quercetin against endothelial cells transformed by Kaposi's sarcoma-associated herpesvirus G protein-coupled receptor. Biochimie 2025; 229:30-41. [PMID: 39369938 DOI: 10.1016/j.biochi.2024.10.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 06/19/2024] [Revised: 09/16/2024] [Accepted: 10/04/2024] [Indexed: 10/08/2024]
Abstract
Quercetin (QUE) is a natural flavonoid with well-known anticancer capabilities, although its effect on viral-induced cancers is less studied. Kaposi's sarcoma (KS) is a viral cancer caused by the human herpesvirus-8, which, during its lytic phase, expresses a constitutively activated viral G protein-coupled receptor (vGPCR) able to induce oncogenic modifications that lead to tumor development. The aim of this work was to investigate the potential effect of QUE on in vitro and in vivo models of Kaposi's sarcoma, developed by transforming endothelial cells with the vGPCR of Kaposi's sarcoma-associated herpesvirus. Initially, the antiproliferative effect of QUE was determined in endothelial cells stably expressing the vGPCR (vGPCR cells), with an IC50 of 30 μM. Additionally, QUE provoked a decrease in vGPCR cell viability, interfered with the cell cycle progression, and induced apoptosis, as revealed by annexin V/PI analysis and caspase-3 activity. The presence of apoptotic bodies and disorganized actin filaments was observed by SEM and phalloidin staining. Furthermore, tumors from vGPCR cells were induced in nude mice, which were treated with QUE (50 or 100 mg/kg/d) resulting in retarded tumor progression and reduced tumor weight. Notably, neither kidney nor liver damage was observed, as indicated by biochemical parameters in serum. In conclusion, this study suggests for the first time that QUE exhibits antineoplastic activity in both in vitro and in vivo models of KS, marking a starting point for further investigations and protocols for therapeutic purpose.
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Affiliation(s)
- Gabriel Principe
- Instituto de Ciencias Biológicas y Biomédicas del Sur (INBIOSUR), Universidad Nacional del Sur (UNS), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Bahía Blanca, Argentina; Departamento de Biología, Bioquímica y Farmacia, UNS, San Juan 670, 8000, Bahía Blanca, Argentina
| | - Virginia Lezcano
- Instituto de Ciencias Biológicas y Biomédicas del Sur (INBIOSUR), Universidad Nacional del Sur (UNS), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Bahía Blanca, Argentina; Departamento de Biología, Bioquímica y Farmacia, UNS, San Juan 670, 8000, Bahía Blanca, Argentina.
| | - Silvina Tiburzi
- Instituto de Ciencias Biológicas y Biomédicas del Sur (INBIOSUR), Universidad Nacional del Sur (UNS), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Bahía Blanca, Argentina; Departamento de Biología, Bioquímica y Farmacia, UNS, San Juan 670, 8000, Bahía Blanca, Argentina
| | - Alicia B Miravalles
- Departamento de Biología, Bioquímica y Farmacia, UNS, San Juan 670, 8000, Bahía Blanca, Argentina
| | - Betina N García
- Departamento de Biología, Bioquímica y Farmacia, UNS, San Juan 670, 8000, Bahía Blanca, Argentina; Bioquímica Austral, Laboratorio de Análisis Clínicos y Gestión, 25 de Mayo 1007, 8000, Bahía Blanca, Argentina
| | - Fernanda Gumilar
- Instituto de Ciencias Biológicas y Biomédicas del Sur (INBIOSUR), Universidad Nacional del Sur (UNS), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Bahía Blanca, Argentina; Departamento de Biología, Bioquímica y Farmacia, UNS, San Juan 670, 8000, Bahía Blanca, Argentina
| | - Verónica González-Pardo
- Instituto de Ciencias Biológicas y Biomédicas del Sur (INBIOSUR), Universidad Nacional del Sur (UNS), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Bahía Blanca, Argentina; Departamento de Biología, Bioquímica y Farmacia, UNS, San Juan 670, 8000, Bahía Blanca, Argentina.
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2
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Gargouri B, Amor IB, Ramma Y, Mansour RB, Bayoudh A, Kallel I, Attia H. Oxidative stress profile and auto-antibodies production in Tunisian patients with COVID-19. Cytotechnology 2025; 77:22. [PMID: 39711970 PMCID: PMC11655737 DOI: 10.1007/s10616-024-00683-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 03/09/2024] [Accepted: 12/07/2024] [Indexed: 12/24/2024] Open
Abstract
The clinical evidence, complications and the pathogenesis of COVID-19 are not clearly understood. In COVID-19 patients, cellular immune response biomarkers and oxidative stress parameters have been used as gravity markers. Indeed, oxidative stress has been proposed to play an essential role in the genesis of COVID-19. In the present research, we investigated lipid peroxidation, protein oxidation, superoxide dismutase activity and the production of auto-antibodies against superoxide dismutase, in the blood of Tunisian patients with corona virus. To evaluate lipid peroxidation, plasma malondialdehyde and conjugated dienes, have been determined in 69 corona virus patients and 30 controls. To determine protein oxidation the thiol level was measured. Plasma superoxide dismutase activity has been measured in 30 corona virus patients and 30 controls on one hand. Utilizing a standard enzyme-linked immunosorbent assay, the level of immunoglobulin G (IgG), and M (IgM) directed against superoxide dismutase was evaluated. To investigate the implication of auto-antibody production in COVID-19 patients in the generation of oxidative stress, a correlation study between auto-antibodies production and oxidative stress parameters was performed. High levels of both malondialdehyde and conjugated dienes were found in the plasma of patients (p < 0.001, respectively). Protein oxidation was confirmed by the high level of thiol (p < 0.001). Superoxide dismutase activity was not significantly lower in COVID-19 patients (p > 0.05). The level of immunoglobulin G (IgG), and M (IgM) directed against superoxide dismutase is significantly higher in COVID-19 patients than in control group (p < 0.001 respectively). Statistical analyses have demonstrated a positive correlation between superoxide dismutase activity and IgM and IgG isotypes antibodies level against superoxide dismutase (p < 0.001). A strong positive correlation was observed between IgG and malondialdehyde level in all cases (r = 0.368; p ≤ 0.01). In addition, a significant positive correlation was noted between IgM and malondialdehyde (r = 0.290; p = 0.024). Similarly, two significant positive relationship was found between IgG / conjugated dienes (r = 0.356; p = 0.005) and between IgM / conjugated dienes (r = 0.285; p = 0.027).
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Affiliation(s)
- Bochra Gargouri
- Laboratory LR11ES45, Research Group“Biotechnology and Pathology”, National School of Engineers of Sfax, Sfax, Tunisia
| | - Ichrak Ben Amor
- Laboratory LR11ES45, Research Group“Biotechnology and Pathology”, National School of Engineers of Sfax, Sfax, Tunisia
| | - Yosra Ramma
- Laboratory LR11ES45, Research Group“Biotechnology and Pathology”, National School of Engineers of Sfax, Sfax, Tunisia
| | | | - Ahmed Bayoudh
- Biological Engineering Department, National School of Engineers of Sfax, University of Sfax, Sfax, Tunisia
| | - Imen Kallel
- Laboratory of Environnemental Toxicology- Microbiology, FSS, Sfax University, Sfax, Tunisia
| | - Hammadi Attia
- Laboratory LR11ES45, Research Group“Biotechnology and Pathology”, National School of Engineers of Sfax, Sfax, Tunisia
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3
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Özdemiral C, Yaz I, Esenboga S, Nabiyeva Cevik N, Bildik HN, Kilic M, Tezcan I, Cagdas D. Human FCHO1 deficiency: review of the literature and additional two cases. Clin Exp Immunol 2025; 219:uxae097. [PMID: 39498505 PMCID: PMC11773606 DOI: 10.1093/cei/uxae097] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 06/02/2024] [Revised: 09/02/2024] [Accepted: 11/04/2024] [Indexed: 01/29/2025] Open
Abstract
F-BAR domain only protein 1 (FCHO1) contributes as a critical component to an essential cellular process, clathrin-mediated endocytosis. Clathrin-mediated endocytosis involves cellular membrane invagination followed by cargo protein recruitment and adaptor protein assembly to form endocytic vesicles and maintains several cellular functions, such as signaling, differentiation, nutrition, absorption, and secretion. We aimed to determine the clinical/immunological findings of FCHO1 deficiency to generate an appropriate medical approach. We present clinical/immunological/genetic findings of two FCHO1 deficiency patients together with recently reported 17 patients. We found two different variants in the patients, one previously defined and one novel homozygous mutation [c.306C > A (p.Tyr102Ter)]. Recurrent sinopulmonary infections occurred in all patients, with viral (63.1%) and fungal (52.6%) infections frequently reported. Lymphopenia and CD4 + T cell lymphopenia are present in 77.7% (14/18) and 100% of patients, respectively. CD8+ T cell number is low in half. Hypogammaglobulinemia and low IgM are present in 83.3% (15/18) and 61.1% (11/18) of patients, respectively. Neurological disorders (Guillian-Barre Syndrome, Moya-Moya disease, encephalitis, and cranial infarction) are common [n = 6 (31.5%)]. Malignancy is present in four (21%) patients, three suffered from diffuse large B cell lymphoma, and one developed Hodgkin lymphoma. Additional clinical and laboratory results from more patients helped to define the characteristics of FCHO1 deficiency. The early application of molecular genetic analysis in CID patients is crucial. Since all transplanted patients were alive, allogeneic hematopoietic stem cell transplantation emerged as a potential curative therapy.
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Affiliation(s)
- Cansu Özdemiral
- Division of Immunology, Department of Pediatrics, Hacettepe University Medical School, Ankara, Türkiye
- İhsan Doğramacı Children’s Hospital, Hacettepe University, Ankara, Türkiye
- Division of Immunology, Department of Pediatric Basic Sciences, Institute of Child Health, Hacettepe University, Ankara, Türkiye
| | - Ismail Yaz
- İhsan Doğramacı Children’s Hospital, Hacettepe University, Ankara, Türkiye
- Division of Immunology, Department of Pediatric Basic Sciences, Institute of Child Health, Hacettepe University, Ankara, Türkiye
| | - Saliha Esenboga
- Division of Immunology, Department of Pediatrics, Hacettepe University Medical School, Ankara, Türkiye
- İhsan Doğramacı Children’s Hospital, Hacettepe University, Ankara, Türkiye
- Division of Immunology, Department of Pediatric Basic Sciences, Institute of Child Health, Hacettepe University, Ankara, Türkiye
| | - Nadira Nabiyeva Cevik
- Division of Immunology, Department of Pediatrics, Hacettepe University Medical School, Ankara, Türkiye
- İhsan Doğramacı Children’s Hospital, Hacettepe University, Ankara, Türkiye
- Division of Immunology, Department of Pediatric Basic Sciences, Institute of Child Health, Hacettepe University, Ankara, Türkiye
| | - Hacer Neslihan Bildik
- Division of Immunology, Department of Pediatrics, Hacettepe University Medical School, Ankara, Türkiye
- Division of Immunology, Department of Pediatric Basic Sciences, Institute of Child Health, Hacettepe University, Ankara, Türkiye
| | - Mehmet Kilic
- Division of Allergy and Immunology, Department of Pediatrics, Fırat University Faculty of Medicine, Elazığ, Türkiye
| | - Ilhan Tezcan
- Division of Immunology, Department of Pediatrics, Hacettepe University Medical School, Ankara, Türkiye
- İhsan Doğramacı Children’s Hospital, Hacettepe University, Ankara, Türkiye
- Division of Immunology, Department of Pediatric Basic Sciences, Institute of Child Health, Hacettepe University, Ankara, Türkiye
| | - Deniz Cagdas
- Division of Immunology, Department of Pediatrics, Hacettepe University Medical School, Ankara, Türkiye
- İhsan Doğramacı Children’s Hospital, Hacettepe University, Ankara, Türkiye
- Division of Immunology, Department of Pediatric Basic Sciences, Institute of Child Health, Hacettepe University, Ankara, Türkiye
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4
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Yao R, Xie C, Xia X. Recent progress in mRNA cancer vaccines. Hum Vaccin Immunother 2024; 20:2307187. [PMID: 38282471 PMCID: PMC10826636 DOI: 10.1080/21645515.2024.2307187] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 09/28/2023] [Accepted: 01/16/2024] [Indexed: 01/30/2024] Open
Abstract
The research and development of messenger RNA (mRNA) cancer vaccines have gradually overcome numerous challenges through the application of personalized cancer antigens, structural optimization of mRNA, and the development of alternative RNA-based vectors and efficient targeted delivery vectors. Clinical trials are currently underway for various cancer vaccines that encode tumor-associated antigens (TAAs), tumor-specific antigens (TSAs), or immunomodulators. In this paper, we summarize the optimization of mRNA and the emergence of RNA-based expression vectors in cancer vaccines. We begin by reviewing the advancement and utilization of state-of-the-art targeted lipid nanoparticles (LNPs), followed by presenting the primary classifications and clinical applications of mRNA cancer vaccines. Collectively, mRNA vaccines are emerging as a central focus in cancer immunotherapy, offering the potential to address multiple challenges in cancer treatment, either as standalone therapies or in combination with current cancer treatments.
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Affiliation(s)
- Ruhui Yao
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Chunyuan Xie
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Xiaojun Xia
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, China
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5
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Martin P, Pardo-Pastor C, Jenkins RG, Rosenblatt J. Imperfect wound healing sets the stage for chronic diseases. Science 2024; 386:eadp2974. [PMID: 39636982 PMCID: PMC7617408 DOI: 10.1126/science.adp2974] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 09/08/2024] [Accepted: 11/05/2024] [Indexed: 12/07/2024]
Abstract
Although the age of the genome gave us much insight about how our organs fail with disease, it also suggested that diseases do not arise from mutations alone; rather, they develop as we age. In this Review, we examine how wound healing might act to ignite disease. Wound healing works well when we are younger, repairing damage from accidents, environmental assaults, and battles with pathogens. Yet, with age and accumulation of mutations and tissue damage, the repair process can devolve, leading to inflammation, fibrosis, and neoplastic signaling. We discuss healthy wound responses and how our bodies might misappropriate these pathways in disease. Although we focus predominantly on epithelial-based (lung and skin) diseases, similar pathways might operate in cardiac, muscle, and neuronal diseases.
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Affiliation(s)
- Paul Martin
- School of Biochemistry, University of Bristol, Bristol, UK
| | - Carlos Pardo-Pastor
- Laboratory of Molecular Physiology, Department of Medicine and Life Sciences, Universitat Pompeu Fabra, Barcelona, Spain
| | - R Gisli Jenkins
- Margaret Turner Warwick Centre for Fibrosing Lung Disease, National Heart & Lung Institute, NIHR Imperial Biomedical Research Centre, Imperial College London, London, UK
| | - Jody Rosenblatt
- The Randall and Cancer Centres King's College London, London, UK
- The Francis Crick Institute, London, UK
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6
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Cao Y, Xia H, Tan X, Shi C, Ma Y, Meng D, Zhou M, Lv Z, Wang S, Jin Y. Intratumoural microbiota: a new frontier in cancer development and therapy. Signal Transduct Target Ther 2024; 9:15. [PMID: 38195689 PMCID: PMC10776793 DOI: 10.1038/s41392-023-01693-0] [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] [Academic Contribution Register] [Received: 05/11/2023] [Revised: 09/20/2023] [Accepted: 10/24/2023] [Indexed: 01/11/2024] Open
Abstract
Human microorganisms, including bacteria, fungi, and viruses, play key roles in several physiological and pathological processes. Some studies discovered that tumour tissues once considered sterile actually host a variety of microorganisms, which have been confirmed to be closely related to oncogenesis. The concept of intratumoural microbiota was subsequently proposed. Microbiota could colonise tumour tissues through mucosal destruction, adjacent tissue migration, and hematogenic invasion and affect the biological behaviour of tumours as an important part of the tumour microenvironment. Mechanistic studies have demonstrated that intratumoural microbiota potentially promote the initiation and progression of tumours by inducing genomic instability and mutations, affecting epigenetic modifications, promoting inflammation response, avoiding immune destruction, regulating metabolism, and activating invasion and metastasis. Since more comprehensive and profound insights about intratumoral microbiota are continuously emerging, new methods for the early diagnosis and prognostic assessment of cancer patients have been under examination. In addition, interventions based on intratumoural microbiota show great potential to open a new chapter in antitumour therapy, especially immunotherapy, although there are some inevitable challenges. Here, we aim to provide an extensive review of the concept, development history, potential sources, heterogeneity, and carcinogenic mechanisms of intratumoural microorganisms, explore the potential role of microorganisms in tumour prognosis, and discuss current antitumour treatment regimens that target intratumoural microorganisms and the research prospects and limitations in this field.
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Affiliation(s)
- Yaqi Cao
- Department of Respiratory and Critical Care Medicine, Hubei Province Clinical Research Center for Major Respiratory Diseases, Key Laboratory of Respiratory Diseases of National Health Commission, State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430022, China
- Hubei Province Engineering Research Center for Tumour-Targeted Biochemotherapy, MOE Key Laboratory of Biological Targeted Therapy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430022, China
- Hubei Province Key Laboratory of Biological Targeted Therapy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430022, China
| | - Hui Xia
- Department of Respiratory and Critical Care Medicine, Hubei Province Clinical Research Center for Major Respiratory Diseases, Key Laboratory of Respiratory Diseases of National Health Commission, State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430022, China
- Hubei Province Engineering Research Center for Tumour-Targeted Biochemotherapy, MOE Key Laboratory of Biological Targeted Therapy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430022, China
- Hubei Province Key Laboratory of Biological Targeted Therapy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430022, China
| | - Xueyun Tan
- Department of Respiratory and Critical Care Medicine, Hubei Province Clinical Research Center for Major Respiratory Diseases, Key Laboratory of Respiratory Diseases of National Health Commission, State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430022, China
- Hubei Province Engineering Research Center for Tumour-Targeted Biochemotherapy, MOE Key Laboratory of Biological Targeted Therapy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430022, China
- Hubei Province Key Laboratory of Biological Targeted Therapy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430022, China
| | - Chunwei Shi
- Department of Pathogen Biology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430022, China
| | - Yanling Ma
- Department of Respiratory and Critical Care Medicine, Hubei Province Clinical Research Center for Major Respiratory Diseases, Key Laboratory of Respiratory Diseases of National Health Commission, State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430022, China
| | - Daquan Meng
- Department of Respiratory and Critical Care Medicine, Hubei Province Clinical Research Center for Major Respiratory Diseases, Key Laboratory of Respiratory Diseases of National Health Commission, State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430022, China
| | - Mengmeng Zhou
- Department of Respiratory and Critical Care Medicine, Hubei Province Clinical Research Center for Major Respiratory Diseases, Key Laboratory of Respiratory Diseases of National Health Commission, State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430022, China
| | - Zhilei Lv
- Department of Respiratory and Critical Care Medicine, Hubei Province Clinical Research Center for Major Respiratory Diseases, Key Laboratory of Respiratory Diseases of National Health Commission, State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430022, China
| | - Sufei Wang
- Department of Respiratory and Critical Care Medicine, Hubei Province Clinical Research Center for Major Respiratory Diseases, Key Laboratory of Respiratory Diseases of National Health Commission, State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430022, China.
- Hubei Province Engineering Research Center for Tumour-Targeted Biochemotherapy, MOE Key Laboratory of Biological Targeted Therapy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430022, China.
- Hubei Province Key Laboratory of Biological Targeted Therapy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430022, China.
| | - Yang Jin
- Department of Respiratory and Critical Care Medicine, Hubei Province Clinical Research Center for Major Respiratory Diseases, Key Laboratory of Respiratory Diseases of National Health Commission, State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430022, China.
- Hubei Province Engineering Research Center for Tumour-Targeted Biochemotherapy, MOE Key Laboratory of Biological Targeted Therapy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430022, China.
- Hubei Province Key Laboratory of Biological Targeted Therapy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430022, China.
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7
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Tavakolian S, Tabaeian SP, Namazi A, Faghihloo E, Akbari A. Role of the VEGF in virus-associated cancers. Rev Med Virol 2024; 34:e2493. [PMID: 38078693 DOI: 10.1002/rmv.2493] [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] [Academic Contribution Register] [Received: 07/12/2023] [Accepted: 11/14/2023] [Indexed: 01/30/2024]
Abstract
The role of numerous risk factors, including consumption of alcohol, smoking, having diet high in fat and sugar and many other items, on caner progression cannot be denied. Viral diseases are one these factors, and they can initiate some signalling pathways causing cancer. For example, they can be effective on providing oxygen and nutrients by inducing VEGF expression. In this review article, we summarised the mechanisms of angiogenesis and VEGF expression in cancerous tissues which are infected with oncoviruses (Epstein-Barr virus, Human papillomavirus infection, Human T-lymphotropic virus, Kaposi's sarcoma-associated herpesvirus, Hepatitis B and hepatitis C virus).
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Affiliation(s)
- Shaian Tavakolian
- The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia
- Department of Medical Biology, The University of Melbourne, Parkville, Victoria, Australia
| | - Seidamir Pasha Tabaeian
- Department of Internal Medicine, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
- Colorectal Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Abolfazl Namazi
- Department of Internal Medicine, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
- Colorectal Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Ebrahim Faghihloo
- Department of Microbiology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Abolfazl Akbari
- Colorectal Research Center, Iran University of Medical Sciences, Tehran, Iran
- Occupational Medicine Research Center, Iran University of Medical Sciences, Tehran, Iran
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8
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Pereira EPV, da Silva Felipe SM, de Freitas RM, da Cruz Freire JE, Oliveira AER, Canabrava N, Soares PM, van Tilburg MF, Guedes MIF, Grueter CE, Ceccatto VM. Transcriptional Profiling of SARS-CoV-2-Infected Calu-3 Cells Reveals Immune-Related Signaling Pathways. Pathogens 2023; 12:1373. [PMID: 38003837 PMCID: PMC10674242 DOI: 10.3390/pathogens12111373] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 09/15/2023] [Revised: 11/11/2023] [Accepted: 11/14/2023] [Indexed: 11/26/2023] Open
Abstract
The COVID-19 disease, caused by the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), emerged in late 2019 and rapidly spread worldwide, becoming a pandemic that infected millions of people and caused significant deaths. COVID-19 continues to be a major threat, and there is a need to deepen our understanding of the virus and its mechanisms of infection. To study the cellular responses to SARS-CoV-2 infection, we performed an RNA sequencing of infected vs. uninfected Calu-3 cells. Total RNA was extracted from infected (0.5 MOI) and control Calu-3 cells and converted to cDNA. Sequencing was performed, and the obtained reads were quality-analyzed and pre-processed. Differential expression was assessed with the EdgeR package, and functional enrichment was performed in EnrichR for Gene Ontology, KEGG pathways, and WikiPathways. A total of 1040 differentially expressed genes were found in infected vs. uninfected Calu-3 cells, of which 695 were up-regulated and 345 were down-regulated. Functional enrichment analyses revealed the predominant up-regulation of genes related to innate immune response, response to virus, inflammation, cell proliferation, and apoptosis. These transcriptional changes following SARS-CoV-2 infection may reflect a cellular response to the infection and help to elucidate COVID-19 pathogenesis, in addition to revealing potential biomarkers and drug targets.
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Affiliation(s)
- Eric Petterson Viana Pereira
- Superior Institute of Biomedical Sciences, State University of Ceará, Fortaleza 60714-903, CE, Brazil; (S.M.d.S.F.); (R.M.d.F.); (J.E.d.C.F.); (P.M.S.)
| | - Stela Mirla da Silva Felipe
- Superior Institute of Biomedical Sciences, State University of Ceará, Fortaleza 60714-903, CE, Brazil; (S.M.d.S.F.); (R.M.d.F.); (J.E.d.C.F.); (P.M.S.)
| | - Raquel Martins de Freitas
- Superior Institute of Biomedical Sciences, State University of Ceará, Fortaleza 60714-903, CE, Brazil; (S.M.d.S.F.); (R.M.d.F.); (J.E.d.C.F.); (P.M.S.)
| | - José Ednésio da Cruz Freire
- Superior Institute of Biomedical Sciences, State University of Ceará, Fortaleza 60714-903, CE, Brazil; (S.M.d.S.F.); (R.M.d.F.); (J.E.d.C.F.); (P.M.S.)
| | | | - Natália Canabrava
- Biotechnology and Molecular Biology Laboratory, State University of Ceará, Fortaleza 60714-903, CE, Brazil; (N.C.); (M.F.v.T.); (M.I.F.G.)
| | - Paula Matias Soares
- Superior Institute of Biomedical Sciences, State University of Ceará, Fortaleza 60714-903, CE, Brazil; (S.M.d.S.F.); (R.M.d.F.); (J.E.d.C.F.); (P.M.S.)
| | - Mauricio Fraga van Tilburg
- Biotechnology and Molecular Biology Laboratory, State University of Ceará, Fortaleza 60714-903, CE, Brazil; (N.C.); (M.F.v.T.); (M.I.F.G.)
| | - Maria Izabel Florindo Guedes
- Biotechnology and Molecular Biology Laboratory, State University of Ceará, Fortaleza 60714-903, CE, Brazil; (N.C.); (M.F.v.T.); (M.I.F.G.)
| | - Chad Eric Grueter
- Department of Internal Medicine, University of Iowa, Iowa City, IA 52242, USA;
| | - Vânia Marilande Ceccatto
- Superior Institute of Biomedical Sciences, State University of Ceará, Fortaleza 60714-903, CE, Brazil; (S.M.d.S.F.); (R.M.d.F.); (J.E.d.C.F.); (P.M.S.)
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9
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Kannampuzha S, Gopalakrishnan AV, Padinharayil H, Alappat RR, Anilkumar KV, George A, Dey A, Vellingiri B, Madhyastha H, Ganesan R, Ramesh T, Jayaraj R, Prabakaran DS. Onco-Pathogen Mediated Cancer Progression and Associated Signaling Pathways in Cancer Development. Pathogens 2023; 12:770. [PMID: 37375460 DOI: 10.3390/pathogens12060770] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 03/11/2023] [Revised: 05/20/2023] [Accepted: 05/23/2023] [Indexed: 06/29/2023] Open
Abstract
Infection with viruses, bacteria, and parasites are thought to be the underlying cause of about 8-17% of the world's cancer burden, i.e., approximately one in every five malignancies globally is caused by an infectious pathogen. Oncogenesis is thought to be aided by eleven major pathogens. It is crucial to identify microorganisms that potentially act as human carcinogens and to understand how exposure to such pathogens occur as well as the following carcinogenic pathways they induce. Gaining knowledge in this field will give important suggestions for effective pathogen-driven cancer care, control, and, ultimately, prevention. This review will mainly focus on the major onco-pathogens and the types of cancer caused by them. It will also discuss the major pathways which, when altered, lead to the progression of these cancers.
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Affiliation(s)
- Sandra Kannampuzha
- Department of Biomedical Sciences, School of Biosciences and Technology, Vellore Institute of Technology (VIT), Vellore 632014, India
| | - Abilash Valsala Gopalakrishnan
- Department of Biomedical Sciences, School of Biosciences and Technology, Vellore Institute of Technology (VIT), Vellore 632014, India
| | - Hafiza Padinharayil
- Jubilee Centre for Medical Research, Jubilee Mission Medical College and Research Institute, Thrissur 680596, India
| | - Reema Rose Alappat
- Jubilee Centre for Medical Research, Jubilee Mission Medical College and Research Institute, Thrissur 680596, India
- Post Graduate and Research Department of Zoology, Maharajas College, Ernakulam 682011, India
| | - Kavya V Anilkumar
- Jubilee Centre for Medical Research, Jubilee Mission Medical College and Research Institute, Thrissur 680596, India
- Post Graduate and Research Department of Zoology, Maharajas College, Ernakulam 682011, India
| | - Alex George
- Jubilee Centre for Medical Research, Jubilee Mission Medical College and Research Institute, Thrissur 680596, India
| | - Abhijit Dey
- Department of Life Sciences, Presidency University, Kolkata 700073, India
| | - Balachandar Vellingiri
- Stem Cell and Regenerative Medicine/Translational Research, Department of Zoology, School of Basic Sciences, Central University of Punjab (CUPB), Bathinda 151401, India
| | - Harishkumar Madhyastha
- Department of Cardiovascular Physiology, Faculty of Medicine, University of Miyazaki, Miyazaki 889-1692, Japan
| | - Raja Ganesan
- Institute for Liver and Digestive Diseases, College of Medicine, Hallym University, Chuncheon 24252, Republic of Korea
| | - Thiyagarajan Ramesh
- Department of Basic Medical Sciences, College of Medicine, Prince Sattam bin Abdulaziz University, P.O. Box 173, Al-Kharj 11942, Saudi Arabia
| | - Rama Jayaraj
- Jindal Institute of Behavioral Sciences (JIBS), Jindal Global Institution of Eminence Deemed to Be University, Sonipat 131001, India
- Director of Clinical Sciences, Northern Territory Institute of Research and Training, Darwin, NT 0909, Australia
| | - D S Prabakaran
- Department of Radiation Oncology, College of Medicine, Chungbuk National University, Chungdae-ro 1, Seowon-gu, Cheongju 28644, Republic of Korea
- Department of Biotechnology, Ayya Nadar Janaki Ammal College, Srivilliputhur Main Road, Sivakasi 626124, India
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10
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Basaran MM, Hazar M, Aydın M, Uzuğ G, Özdoğan İ, Pala E, Aydın Dilsiz S, Basaran N. Effects of COVID-19 Disease on DNA Damage, Oxidative Stress and Immune Responses. TOXICS 2023; 11:386. [PMID: 37112613 PMCID: PMC10145820 DOI: 10.3390/toxics11040386] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Academic Contribution Register] [Received: 03/28/2023] [Revised: 04/10/2023] [Accepted: 04/17/2023] [Indexed: 06/19/2023]
Abstract
Coronavirus disease 2019 (COVID-19) has posed a great threat to public health and has caused concern due to its fatal consequences over the last few years. Most people with COVID-19 show mild-to-moderate symptoms and recover without the need for special treatment, while others become seriously ill and need medical attention. Additionally, some serious outcomes, such as heart attacks and even stroke, have been later reported in patients who had recovered. There are limited studies on how SARS-CoV-2 infection affects some molecular pathways, including oxidative stress and DNA damage. In this study, we aimed to evaluate DNA damage, using the alkaline comet assay, and its relationship with oxidative stress and immune response parameters in COVID-19-positive patients. Our results show that DNA damage, oxidative stress parameters and cytokine levels significantly increased in SARS-CoV-2-positive patients when compared with healthy controls. The effects of SARS-CoV-2 infection on DNA damage, oxidative stress and immune responses may be crucial in the pathophysiology of the disease. It is suggested that the illumination of these pathways will contribute to the development of clinical treatments and to reduce adverse effects in the future.
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Affiliation(s)
- M. Mert Basaran
- Department of Otolaryngology, Faculty of Medicine, Kafkas University, 36000 Kars, Türkiye
| | - Merve Hazar
- Department of Pharmaceutical Toxicology, Faculty of Pharmacy, İbrahim Cecen University, 04100 Ağrı, Türkiye;
- Department of Pharmaceutical Toxicology, Faculty of Pharmacy, Hacettepe University, 06100 Ankara, Türkiye;
| | - Mehtap Aydın
- Department of Infectious Diseases and Clinical Microbiology, Health Sciences University, Ümraniye Training and Research Hospital, 34764 İstanbul, Türkiye; (M.A.); (G.U.); (İ.Ö.)
| | - Gülsüm Uzuğ
- Department of Infectious Diseases and Clinical Microbiology, Health Sciences University, Ümraniye Training and Research Hospital, 34764 İstanbul, Türkiye; (M.A.); (G.U.); (İ.Ö.)
| | - İlkima Özdoğan
- Department of Infectious Diseases and Clinical Microbiology, Health Sciences University, Ümraniye Training and Research Hospital, 34764 İstanbul, Türkiye; (M.A.); (G.U.); (İ.Ö.)
| | - Emin Pala
- Department of Family Medicine, Health Sciences University, Ümraniye Training and Research Hospital, 34764 İstanbul, Türkiye;
| | - Sevtap Aydın Dilsiz
- Department of Pharmaceutical Toxicology, Faculty of Pharmacy, Hacettepe University, 06100 Ankara, Türkiye;
| | - Nursen Basaran
- Department of Pharmaceutical Toxicology, Faculty of Pharmacy, Başkent University, 06490 Ankara, Türkiye
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11
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In Vitro Studies of Pegylated Magnetite Nanoparticles in a Cellular Model of Viral Oncogenesis: Initial Studies to Evaluate Their Potential as a Future Theranostic Tool. Pharmaceutics 2023; 15:pharmaceutics15020488. [PMID: 36839809 PMCID: PMC9967771 DOI: 10.3390/pharmaceutics15020488] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 12/07/2022] [Revised: 01/17/2023] [Accepted: 01/29/2023] [Indexed: 02/05/2023] Open
Abstract
Magnetic nanosystems represent promising alternatives to the traditional diagnostic and treatment procedures available for different pathologies. In this work, a series of biological tests are proposed, aiming to validate a magnetic nanoplatform for Kaposi's sarcoma treatment. The selected nanosystems were polyethylene glycol-coated iron oxide nanoparticles (MAG.PEG), which were prepared by the hydrothermal method. Physicochemical characterization was performed to verify their suitable physicochemical properties to be administered in vivo. Exhaustive biological assays were conducted, aiming to validate this platform in a specific biomedical field related to viral oncogenesis diseases. As a first step, the MAG.PEG cytotoxicity was evaluated in a cellular model of Kaposi's sarcoma. By phase contrast microscopy, it was found that cell morphology remained unchanged regardless of the nanoparticles' concentration (1-150 µg mL-1). The results, arising from the crystal violet technique, revealed that the proliferation was also unaffected. In addition, cell viability analysis by MTS and neutral red assays revealed a significant increase in metabolic and lysosomal activity at high concentrations of MAG.PEG (100-150 µg mL-1). Moreover, an increase in ROS levels was observed at the highest concentration of MAG.PEG. Second, the iron quantification assays performed by Prussian blue staining showed that MAG.PEG cellular accumulation is dose dependent. Furthermore, the presence of vesicles containing MAG.PEG inside the cells was confirmed by TEM. Finally, the MAG.PEG steering was achieved using a static magnetic field generated by a moderate power magnet. In conclusion, MAG.PEG at a moderate concentration would be a suitable drug carrier for Kaposi's sarcoma treatment, avoiding adverse effects on normal tissues. The data included in this contribution appear as the first stage in proposing this platform as a suitable future theranostic to improve Kaposi's sarcoma therapy.
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12
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Protein Kinase CK2 and Epstein-Barr Virus. Biomedicines 2023; 11:biomedicines11020358. [PMID: 36830895 PMCID: PMC9953236 DOI: 10.3390/biomedicines11020358] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 12/16/2022] [Revised: 01/20/2023] [Accepted: 01/24/2023] [Indexed: 01/28/2023] Open
Abstract
Protein kinase CK2 is a pleiotropic protein kinase, which phosphorylates a number of cellular and viral proteins. Thereby, this kinase is implicated in the regulation of cellular signaling, controlling of cell proliferation, apoptosis, angiogenesis, immune response, migration and invasion. In general, viruses use host signaling mechanisms for the replication of their genome as well as for cell transformation leading to cancer. Therefore, it is not surprising that CK2 also plays a role in controlling viral infection and the generation of cancer cells. Epstein-Barr virus (EBV) lytically infects epithelial cells of the oropharynx and B cells. These latently infected B cells subsequently become resting memory B cells when passing the germinal center. Importantly, EBV is responsible for the generation of tumors such as Burkitt's lymphoma. EBV was one of the first human viruses, which was connected to CK2 in the early nineties of the last century. The present review shows that protein kinase CK2 phosphorylates EBV encoded proteins as well as cellular proteins, which are implicated in the lytic and persistent infection and in EBV-induced neoplastic transformation. EBV-encoded and CK2-phosphorylated proteins together with CK2-phosphorylated cellular signaling proteins have the potential to provide efficient virus replication and cell transformation. Since there are powerful inhibitors known for CK2 kinase activity, CK2 might become an attractive target for the inhibition of EBV replication and cell transformation.
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13
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Bouyahya A, El Allam A, Aboulaghras S, Bakrim S, El Menyiy N, Alshahrani MM, Al Awadh AA, Benali T, Lee LH, El Omari N, Goh KW, Ming LC, Mubarak MS. Targeting mTOR as a Cancer Therapy: Recent Advances in Natural Bioactive Compounds and Immunotherapy. Cancers (Basel) 2022; 14:5520. [PMID: 36428613 PMCID: PMC9688668 DOI: 10.3390/cancers14225520] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 10/04/2022] [Revised: 11/01/2022] [Accepted: 11/02/2022] [Indexed: 11/12/2022] Open
Abstract
The mammalian target of rapamycin (mTOR) is a highly conserved serine/threonine-protein kinase, which regulates many biological processes related to metabolism, cancer, immune function, and aging. It is an essential protein kinase that belongs to the phosphoinositide-3-kinase (PI3K) family and has two known signaling complexes, mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2). Even though mTOR signaling plays a critical role in promoting mitochondria-related protein synthesis, suppressing the catabolic process of autophagy, contributing to lipid metabolism, engaging in ribosome formation, and acting as a critical regulator of mRNA translation, it remains one of the significant signaling systems involved in the tumor process, particularly in apoptosis, cell cycle, and cancer cell proliferation. Therefore, the mTOR signaling system could be suggested as a cancer biomarker, and its targeting is important in anti-tumor therapy research. Indeed, its dysregulation is involved in different types of cancers such as colon, neck, cervical, head, lung, breast, reproductive, and bone cancers, as well as nasopharyngeal carcinoma. Moreover, recent investigations showed that targeting mTOR could be considered as cancer therapy. Accordingly, this review presents an overview of recent developments associated with the mTOR signaling pathway and its molecular involvement in various human cancer types. It also summarizes the research progress of different mTOR inhibitors, including natural and synthetised compounds and their main mechanisms, as well as the rational combinations with immunotherapies.
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Affiliation(s)
- Abdelhakim Bouyahya
- Laboratory of Human Pathologies Biology, Department of Biology, Faculty of Sciences, Faculty of Medicine and Pharmacy, Mohammed V University in Rabat, Rabat 10106, Morocco
| | - Aicha El Allam
- Department of Immunology, Yale University School of Medicine, 333 Cedars Street, TAC S610, New Haven, CT 06519, USA
| | - Sara Aboulaghras
- Physiology and Physiopathology Team, Faculty of Sciences, Genomic of Human Pathologies Research, Mohammed V University in Rabat, Rabat 10106, Morocco
| | - Saad Bakrim
- Geo-Bio-Environment Engineering and Innovation Laboratory, Molecular Engineering, Biotechnologies and Innovation Team, Polydisciplinary Faculty of Taroudant, Ibn Zohr University, Agadir 80000, Morocco
| | - Naoual El Menyiy
- Laboratory of Pharmacology, National Agency of Medicinal and Aromatic Plants, Taounate 34025, Morocco
| | - Mohammed Merae Alshahrani
- Department of Clinical Laboratory Sciences, Faculty of Applied Medical Sciences, Najran University, 1988, Najran 61441, Saudi Arabia
| | - Ahmed Abdullah Al Awadh
- Department of Clinical Laboratory Sciences, Faculty of Applied Medical Sciences, Najran University, 1988, Najran 61441, Saudi Arabia
| | - Taoufiq Benali
- Environment and Health Team, Polydisciplinary Faculty of Safi, Cadi Ayyad University, Sidi Bouzid B.P. 4162, Morocco
| | - Learn-Han Lee
- Novel Bacteria and Drug Discovery Research Group (NBDD), Microbiome and Bioresource Research Strength (MBRS), Jeffrey Cheah School of Medicine and Health Sciences, Monash University Malaysia, Bandar Sunway 47500, Malaysia
| | - Nasreddine El Omari
- Laboratory of Histology, Embryology, and Cytogenetic, Faculty of Medicine and Pharmacy, Mohammed V University, Rabat 10100, Morocco
| | - Khang Wen Goh
- Faculty of Data Science and Information Technology, INTI International University, Nilai 71800, Malaysia
| | - Long Chiau Ming
- Pengiran Anak Puteri Rashidah Sa’adatul Bolkiah Institute of Health Sciences, Universiti Brunei Darussalam, Gadong BE1410, Brunei
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Nagel R, Pataskar A, Champagne J, Agami R. Boosting Antitumor Immunity with an Expanded Neoepitope Landscape. Cancer Res 2022; 82:3637-3649. [PMID: 35904353 PMCID: PMC9574376 DOI: 10.1158/0008-5472.can-22-1525] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 05/10/2022] [Revised: 07/07/2022] [Accepted: 07/21/2022] [Indexed: 01/07/2023]
Abstract
Immune-checkpoint blockade therapy has been successfully applied to many cancers, particularly tumors that harbor a high mutational burden and consequently express a high abundance of neoantigens. However, novel approaches are needed to improve the efficacy of immunotherapy for treating tumors that lack a high load of classic genetically derived neoantigens. Recent discoveries of broad classes of nongenetically encoded and inducible neoepitopes open up new avenues for therapeutic development to enhance sensitivity to immunotherapies. In this review, we discuss recent work on neoantigen discovery, with an emphasis on novel classes of noncanonical neoepitopes.
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Affiliation(s)
- Remco Nagel
- Division of Oncogenomics, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, the Netherlands
| | - Abhijeet Pataskar
- Division of Oncogenomics, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, the Netherlands
| | - Julien Champagne
- Division of Oncogenomics, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, the Netherlands
| | - Reuven Agami
- Division of Oncogenomics, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, the Netherlands
- Erasmus MC, Rotterdam University, Rotterdam, the Netherlands
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15
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Aarthy M, Muthuramalingam P, Ramesh M, Singh SK. Unraveling the multi-targeted curative potential of bioactive molecules against cervical cancer through integrated omics and systems pharmacology approach. Sci Rep 2022; 12:14245. [PMID: 35989375 PMCID: PMC9393168 DOI: 10.1038/s41598-022-18358-7] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 01/13/2022] [Accepted: 08/10/2022] [Indexed: 11/09/2022] Open
Abstract
Molecular level understanding on the role of viral infections causing cervical cancer is highly essential for therapeutic development. In these instances, systems pharmacology along with multi omics approach helps in unraveling the multi-targeted mechanisms of novel biologically active compounds to combat cervical cancer. The immuno-transcriptomic dataset of healthy and infected cervical cancer patients was retrieved from the array express. Further, the phytocompounds from medicinal plants were collected from the literature. Network Analyst 3.0 has been used to identify the immune genes around 384 which are differentially expressed and responsible for cervical cancer. Among the 87 compounds reported in plants for treating cervical cancer, only 79 compounds were targeting the identified immune genes of cervical cancer. The significant genes responsible for the domination in cervical cancer are identified in this study. The virogenomic signatures observed from cervical cancer caused by E7 oncoproteins serve as the potential therapeutic targets whereas, the identified compounds can act as anti-HPV drug deliveries. In future, the exploratory rationale of the acquired results will be useful in optimizing small molecules which can be a viable drug candidate.
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16
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Vieira GV, Somera dos Santos F, Lepique AP, da Fonseca CK, Innocentini LMAR, Braz-Silva PH, Quintana SM, Sales KU. Proteases and HPV-Induced Carcinogenesis. Cancers (Basel) 2022; 14:cancers14133038. [PMID: 35804810 PMCID: PMC9264903 DOI: 10.3390/cancers14133038] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 05/05/2022] [Revised: 06/01/2022] [Accepted: 06/15/2022] [Indexed: 02/04/2023] Open
Abstract
Simple Summary Human papillomavirus (HPV) infection is a sexually transmitted disease with high prevalence worldwide. Although most HPV infections do not lead to cancer, some HPV types are correlated with the majority of cervical cancers, and with some anogenital and oropharyngeal cancers. Moreover, enzymes known as proteases play an essential role in the pathogenic process in HPV-induced carcinogenesis. This review highlights the role of proteases and recent epidemiological data regarding HPV-dependent carcinogenesis. Abstract Persistent infection with Human papillomavirus (HPV) is the main etiologic factor for pre-malignant and malignant cervical lesions. Moreover, HPV is also associated with oropharynx and other anogenital carcinomas. Cancer-causing HPV viruses classified as group 1 carcinogens include 12 HPV types, with HPV 16 and 18 being the most prevalent. High-risk HPVs express two oncoproteins, E6 and E7, the products of which are responsible for the inhibition of p53 and pRB proteins, respectively, in human keratinocytes and cellular immortalization. p53 and pRB are pleiotropic proteins that regulate the activity of several signaling pathways and gene expression. Among the important factors that are augmented in HPV-mediated carcinogenesis, proteases not only control processes involved in cellular carcinogenesis but also control the microenvironment. For instance, genetic polymorphisms of matrix metalloproteinase 1 (MMP-1) are associated with carcinoma invasiveness. Similarly, the serine protease inhibitors hepatocyte growth factor activator inhibitor-1 (HAI-1) and -2 (HAI-2) have been identified as prognostic markers for HPV-dependent cervical carcinomas. This review highlights the most crucial mechanisms involved in HPV-dependent carcinogenesis, and includes a section on the proteolytic cascades that are important for the progression of this disease and their impact on patient health, treatment, and survival.
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Affiliation(s)
- Gabriel Viliod Vieira
- Department of Cell and Molecular Biology and Pathogenic Bioagents, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto 14049-900, SP, Brazil; (G.V.V.); (C.K.d.F.); (L.M.A.R.I.)
| | - Fernanda Somera dos Santos
- Department of Gynecology and Obstetrics, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto 14049-900, SP, Brazil; (F.S.d.S.); (S.M.Q.)
| | - Ana Paula Lepique
- Department of Immunology, Biomedical Sciences Institute, University of Sao Paulo, Sao Paulo 05508-000, SP, Brazil;
| | - Carol Kobori da Fonseca
- Department of Cell and Molecular Biology and Pathogenic Bioagents, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto 14049-900, SP, Brazil; (G.V.V.); (C.K.d.F.); (L.M.A.R.I.)
| | - Lara Maria Alencar Ramos Innocentini
- Department of Cell and Molecular Biology and Pathogenic Bioagents, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto 14049-900, SP, Brazil; (G.V.V.); (C.K.d.F.); (L.M.A.R.I.)
- Clinical Hospital of Ribeirao Preto Medical School, University of São Paulo, Ribeirao Preto 14049-900, SP, Brazil
| | - Paulo Henrique Braz-Silva
- Department of Stomatology, School of Dentistry, University of Sao Paulo, São Paulo 05508-000, SP, Brazil;
- Laboratory of Virology, Institute of Tropical Medicine of Sao Paulo, School of Medicine, University of Sao Paulo, Sao Paulo 05403-000, SP, Brazil
| | - Silvana Maria Quintana
- Department of Gynecology and Obstetrics, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto 14049-900, SP, Brazil; (F.S.d.S.); (S.M.Q.)
| | - Katiuchia Uzzun Sales
- Department of Cell and Molecular Biology and Pathogenic Bioagents, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto 14049-900, SP, Brazil; (G.V.V.); (C.K.d.F.); (L.M.A.R.I.)
- Correspondence: ; Tel.: +55-16-3315-9113
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17
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Scott S, Hallwirth CV, Hartkopf F, Grigson S, Jain Y, Alexander IE, Bauer DC, O W Wilson L. Isling: a tool for detecting integration of wild-type viruses and clinical vectors. J Mol Biol 2021; 434:167408. [PMID: 34929203 DOI: 10.1016/j.jmb.2021.167408] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 09/30/2021] [Revised: 12/09/2021] [Accepted: 12/13/2021] [Indexed: 10/19/2022]
Abstract
Detecting viral and vector integration events is a key step when investigating interactions between viral and host genomes. This is relevant in several fields, including virology, cancer research and gene therapy. For example, investigating integrations of wild-type viruses such as human papillomavirus and hepatitis B virus has proven to be crucial for understanding the role of these integrations in cancer. Furthermore, identifying the extent of vector integration is vital for determining the potential for genotoxicity in gene therapies. To address these questions, we developed isling, the first tool specifically designed for identifying viral integrations in both wild-type and vector from next-generation sequencing data. Isling addresses complexities in integration behaviour including integration of fragmented genomes and integration junctions with ambiguous locations in a host or vector genome, and can also flag possible vector recombinations. We show that isling is up to 1.6-fold faster and up to 170% more accurate than other viral integration tools, and performs well on both simulated and real datasets. Isling is therefore an efficient and application-agnostic tool that will enable a broad range of investigations into viral and vector integration. These include comparisons between integrations of wild-type viruses and gene therapy vectors, as well as assessing the genotoxicity of vectors and understanding the role of viruses in cancer.
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Affiliation(s)
- Suzanne Scott
- Australian e-Health Research Centre, Commonwealth Scientific and Industrial Research Organisation, North Ryde, Australia; Gene Therapy Research Unit, Children's Medical Research Institute, Westmead, Australia; The Sydney Children's Hospitals Network, Faculty of Medicine and Health, The University of Sydney, Westmead, Australia
| | - Claus V Hallwirth
- Gene Therapy Research Unit, Children's Medical Research Institute, Westmead, Australia; The Sydney Children's Hospitals Network, Faculty of Medicine and Health, The University of Sydney, Westmead, Australia
| | - Felix Hartkopf
- Department of Mathematics and Computer Science, Freie Universität Berlin, Berlin, Germany
| | - Susanna Grigson
- College of Science and Engineering, Flinders University, Adelaide, Australia
| | - Yatish Jain
- Australian e-Health Research Centre, Commonwealth Scientific and Industrial Research Organisation, North Ryde, Australia
| | - Ian E Alexander
- Gene Therapy Research Unit, Children's Medical Research Institute, Westmead, Australia; The Sydney Children's Hospitals Network, Faculty of Medicine and Health, The University of Sydney, Westmead, Australia; Discipline of Child and Adolescent Health,Faculty of Medicine and Health,The University of Sydney, Sydney, New South Wales, Australia
| | - Denis C Bauer
- Australian e-Health Research Centre, Commonwealth Scientific and Industrial Research Organisation, North Ryde, Australia; Discipline of Child and Adolescent Health,Faculty of Medicine and Health,The University of Sydney, Sydney, New South Wales, Australia; Macquarie University, Department of Biomedical Sciences, Faculty of Medicine and Health Science, Macquarie Park, Australia.
| | - Laurence O W Wilson
- Australian e-Health Research Centre, Commonwealth Scientific and Industrial Research Organisation, North Ryde, Australia; Macquarie University, Applied BioSciences, Faculty of Science and Engineering, Macquarie Park, Australia.
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18
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Liu B, Zhang Q, Wang J, Cao S, Zhou Z, Liu ZX, Cheng H. iCAV: an integrative database of cancer-associated viruses. Database (Oxford) 2021; 2021:6461900. [PMID: 34907423 PMCID: PMC8725190 DOI: 10.1093/database/baab079] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 07/14/2021] [Revised: 11/12/2021] [Accepted: 12/07/2021] [Indexed: 11/12/2022]
Abstract
To date, various studies have found that the occurrence of cancer may be related to viral
infections. Therefore, it is important to explore the relationship between viruses and
diseases. The International Agency for Research on Cancer has defined six types of viruses
as Class 1 human carcinogens, including Epstein–Barr virus, hepatitis C virus, hepatitis B
virus, human T-cell lymphotropic virus, human herpesvirus 8 and human papillomavirus,
while Merkel cell polyomavirus is classified as ‘probably carcinogenic to humans’ (Group
2A). Therefore, in-depth research on these viruses will help clarify their relationship
with diseases, and substantial efforts have been made to sequence their genomes. However,
there is no complete database documenting these cancer-associated viruses, and researchers
are not able to easily access and retrieve the published genomes. In this study, we
developed iCAV, a database that integrates the genomes of cancer-related viruses and the
corresponding phenotypes. We collected a total of 18 649 genome sequences from seven human
disease-related viruses, and each virus was further classified by the associated disease,
sample and country. iCAV is a comprehensive resource of cancer-associated viruses that
provides browse and download functions for viral genomes. Database URL: http://icav.omicsbio.info/
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Affiliation(s)
- Bo Liu
- School of Life Sciences, Zhengzhou University, Zhengzhou 450001, China
| | - Qingfeng Zhang
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou 510060, China
| | - Jingou Wang
- School of Life Sciences, Zhengzhou University, Zhengzhou 450001, China
| | - Shumin Cao
- School of Life Sciences, Zhengzhou University, Zhengzhou 450001, China
| | - Zhiyuan Zhou
- School of Life Sciences, Zhengzhou University, Zhengzhou 450001, China
| | - Ze-Xian Liu
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou 510060, China
| | - Han Cheng
- School of Life Sciences, Zhengzhou University, Zhengzhou 450001, China
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19
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Gopalakrishnan Mahalingam KK, Sankar LS, Masthan K, Mahalakshmi K, Naveen Kumar V. Epstein- Barr viral load in exfoliated cells of oral squamous cell carcinoma and oral potentially malignant disorders - A cross-sectional study. JOURNAL OF CLINICAL VIROLOGY PLUS 2021. [DOI: 10.1016/j.jcvp.2021.100051] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Indexed: 11/26/2022] Open
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Senevirathne A, Hewawaduge C, Lee JH. Genetic interference exerted by Salmonella-delivered CRISPR/Cas9 significantly reduces the pathological burden caused by Marek's disease virus in chickens. Vet Res 2021; 52:125. [PMID: 34593043 PMCID: PMC8482593 DOI: 10.1186/s13567-021-00995-x] [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] [Academic Contribution Register] [Received: 03/10/2021] [Accepted: 08/09/2021] [Indexed: 11/29/2022] Open
Abstract
Efficient in vivo delivery of a CRISPR/Cas9 plasmid is of paramount importance for effective therapy. Here, we investigated the usability of Salmonella as a plasmid carrier for in vivo therapy against virus-induced cancer using Marek’s disease virus (MDV) as a model for study in chickens. A green fluorescent protein-expressing CRISPR/Cas9 plasmid encoding the virulence gene pp38 was constructed against Marek’s disease virus. Therapeutic plasmids were transformed into Salmonella carrying lon and sifA gene deletions. The animals in 5 groups were intraperitoneally inoculated with phosphate-buffered saline, vector control, or Salmonella before or after MDV infection, or left uninfected as a naïve control. Therapeutic effectiveness was evaluated by observing disease outcomes and the viral copy number in peripheral blood mononuclear cells. The efficacy of plasmid delivery by Salmonella was 13 ± 1.7% in the spleen and 8.0 ± 1.8% in the liver on the 6th day post-infection. The Salmonella-treated groups showed significant resistance to MDV infection. The maximum effect was observed in the group treated with Salmonella before MDV infection. None of the chickens fully recovered; however, the results suggested that timely delivery of Salmonella could be effective for in vivo CRISPR/Cas9-mediated genetic interference against highly pathogenic MDV. The use of Salmonella in CRISPR systems provides a simpler and more efficient platform for in vivo therapy with CRISPR than the use of conventional in vivo gene delivery methods and warrants further development.
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Affiliation(s)
- Amal Senevirathne
- College of Veterinary Medicine, Chonbuk National University, Iksan Campus, 54596, Iksan, Republic of Korea
| | - Chamith Hewawaduge
- College of Veterinary Medicine, Chonbuk National University, Iksan Campus, 54596, Iksan, Republic of Korea
| | - John Hwa Lee
- College of Veterinary Medicine, Chonbuk National University, Iksan Campus, 54596, Iksan, Republic of Korea.
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Menati Rashno M, Mehraban H, Naji B, Radmehr M. Microbiome in human cancers. Access Microbiol 2021; 3:000247. [PMID: 34888478 PMCID: PMC8650843 DOI: 10.1099/acmi.0.000247] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 09/18/2020] [Accepted: 06/17/2021] [Indexed: 12/19/2022] Open
Abstract
A microbiome is defined as the aggregate of all microbiota that reside in human digestive system and other tissues. This microbiota includes viruses, bacteria, fungi that live in various human organs and tissues like stomach, guts, oesophagus, mouth cavity, urinary tract, vagina, lungs, and skin. Almost 20 % of malignant cancers worldwide are related to microbial infections including bacteria, parasites, and viruses. The human body is constantly being attacked by microbes during its lifetime and microbial pathogens that have tumorigenic effects in 15-20 % of reported cancer cases. Recent scientific advances and the discovery of the effect of microbes on cancer as a pathogen or as a drug have significantly contributed to our understanding of the complex relationship between microbiome and cancer. The aim of this study is to overview some microbiomes that reside in the human body and their roles in cancer.
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Affiliation(s)
| | - Hamed Mehraban
- Department of Biology, Payame Noor University (PNU), Tehran, Iran
| | - Behnaz Naji
- Department of Microbiology, Damghan Branch, Islamic Azad University, Damghan, Iran
| | - Mohadeseh Radmehr
- Department of Microbiology, Damghan Branch, Islamic Azad University, Damghan, Iran
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22
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Xu H, Jia P, Zhao Z. DeepVISP: Deep Learning for Virus Site Integration Prediction and Motif Discovery. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2021; 8:2004958. [PMID: 33977077 PMCID: PMC8097320 DOI: 10.1002/advs.202004958] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Academic Contribution Register] [Received: 12/23/2020] [Indexed: 05/08/2023]
Abstract
Approximately 15% of human cancers are estimated to be attributed to viruses. Virus sequences can be integrated into the host genome, leading to genomic instability and carcinogenesis. Here, a new deep convolutional neural network (CNN) model is developed with attention architecture, namely DeepVISP, for accurately predicting oncogenic virus integration sites (VISs) in the human genome. Using the curated benchmark integration data of three viruses, hepatitis B virus (HBV), human herpesvirus (HPV), and Epstein-Barr virus (EBV), DeepVISP achieves high accuracy and robust performance for all three viruses through automatically learning informative features and essential genomic positions only from the DNA sequences. In comparison, DeepVISP outperforms conventional machine learning methods by 8.43-34.33% measured by area under curve (AUC) value enhancement in three viruses. Moreover, DeepVISP can decode cis-regulatory factors that are potentially involved in virus integration and tumorigenesis, such as HOXB7, IKZF1, and LHX6. These findings are supported by multiple lines of evidence in literature. The clustering analysis of the informative motifs reveales that the representative k-mers in clusters could help guide virus recognition of the host genes. A user-friendly web server is developed for predicting putative oncogenic VISs in the human genome using DeepVISP.
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Affiliation(s)
- Haodong Xu
- Center for Precision HealthSchool of Biomedical InformaticsThe University of Texas Health Science Center at Houston (UTHealth)HoustonTX77030USA
| | - Peilin Jia
- Center for Precision HealthSchool of Biomedical InformaticsThe University of Texas Health Science Center at Houston (UTHealth)HoustonTX77030USA
| | - Zhongming Zhao
- Center for Precision HealthSchool of Biomedical InformaticsThe University of Texas Health Science Center at Houston (UTHealth)HoustonTX77030USA
- MD Anderson Cancer Center UTHealth Graduate School of Biomedical SciencesHoustonTX77030USA
- Department of Biomedical InformaticsVanderbilt University Medical CenterNashvilleTN37203USA
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23
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Tiri A, Masetti R, Conti F, Tignanelli A, Turrini E, Bertolini P, Esposito S, Pession A. Inborn Errors of Immunity and Cancer. BIOLOGY 2021; 10:biology10040313. [PMID: 33918597 PMCID: PMC8069273 DOI: 10.3390/biology10040313] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Academic Contribution Register] [Received: 03/02/2021] [Revised: 03/30/2021] [Accepted: 04/06/2021] [Indexed: 12/17/2022]
Abstract
Simple Summary Inborn Errors of Immunity (IEI) are a heterogeneous group of disorders characterized by a defect in the function of at least one, and often more, components of the immune system. The overall risk for cancer in children with IEI ranges from 4 to 25%. Several factors, namely, age of the patient, viral infection status and IEI type can influence the development of different cancer types. Immunologists and oncologists should interact to monitor and promptly diagnose the potential development of cancer in known IEI patients, as well as an underlying IEI in newly diagnosed cancers with suggestive medical history or high rate of therapy-related toxicity. The creation of an international registry of IEI cases with detailed information on the occurrence of cancer is fundamental to optimizing the diagnostic process and to evaluating the outcomes of new therapeutic options, with the aim of improving prognosis and reducing comorbidities. Abstract Inborn Errors of Immunity (IEI) are a heterogeneous group of disorders characterized by a defect in the function of at least one, and often more, components of the immune system. The aim of this narrative review is to discuss the epidemiology, the pathogenesis and the correct management of tumours in patients with IEI. PubMed was used to search for all of the studies published over the last 20 years using the keywords: “inborn errors of immunity” or “primary immunodeficiency” and “cancer” or “tumour” or “malignancy”. Literature analysis showed that the overall risk for cancer in children with IEI ranges from 4 to 25%. Several factors, namely, age of the patient, viral infection status and IEI type can influence the development of different cancer types. The knowledge of a specific tumour risk in the presence of IEI highlights the importance of a synergistic effort by immunologists and oncologists in tracking down the potential development of cancer in known IEI patients, as well as an underlying IEI in patients with newly diagnosed cancers. In the current genomic era, the creation of an international registry of IEI cases integrated with malignancies occurrence information is fundamental to optimizing the diagnostic process and to evaluating the outcomes of new therapeutic options, with the hope to obtain a better prognosis for these patients.
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Affiliation(s)
- Alessandra Tiri
- Pediatric Clinic, Pietro Barilla Children’s Hospital, University of Parma, 43126 Parma, Italy; (A.T.); (A.T.); (E.T.)
| | - Riccardo Masetti
- Pediatric Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, University of Bologna, 40138 Bologna, Italy; (R.M.); (F.C.); (A.P.)
| | - Francesca Conti
- Pediatric Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, University of Bologna, 40138 Bologna, Italy; (R.M.); (F.C.); (A.P.)
| | - Anna Tignanelli
- Pediatric Clinic, Pietro Barilla Children’s Hospital, University of Parma, 43126 Parma, Italy; (A.T.); (A.T.); (E.T.)
| | - Elena Turrini
- Pediatric Clinic, Pietro Barilla Children’s Hospital, University of Parma, 43126 Parma, Italy; (A.T.); (A.T.); (E.T.)
| | - Patrizia Bertolini
- Pediatric Oncohematology Unit, Pietro Barilla Children’s Hospital, 43126 Parma, Italy;
| | - Susanna Esposito
- Pediatric Clinic, Pietro Barilla Children’s Hospital, University of Parma, 43126 Parma, Italy; (A.T.); (A.T.); (E.T.)
- Correspondence: ; Tel.: +39-0521-903-524
| | - Andrea Pession
- Pediatric Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, University of Bologna, 40138 Bologna, Italy; (R.M.); (F.C.); (A.P.)
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Garcia-Oliveira P, Otero P, Pereira AG, Chamorro F, Carpena M, Echave J, Fraga-Corral M, Simal-Gandara J, Prieto MA. Status and Challenges of Plant-Anticancer Compounds in Cancer Treatment. Pharmaceuticals (Basel) 2021; 14:ph14020157. [PMID: 33673021 PMCID: PMC7918405 DOI: 10.3390/ph14020157] [Citation(s) in RCA: 111] [Impact Index Per Article: 27.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 12/31/2020] [Revised: 02/03/2021] [Accepted: 02/06/2021] [Indexed: 12/12/2022] Open
Abstract
Nowadays, cancer is one of the deadliest diseases in the world, which has been estimated to cause 9.9 million deaths in 2020. Conventional treatments for cancer commonly involve mono-chemotherapy or a combination of radiotherapy and mono-chemotherapy. However, the negative side effects of these approaches have been extensively reported and have prompted the search of new therapeutic drugs. In this context, scientific community started to look for innovative sources of anticancer compounds in natural sources, including traditional plants. Currently, numerous studies have evaluated the anticancer properties of natural compounds derived from plants, both in vitro and in vivo. In pre-clinical stages, some promising compounds could be mentioned, such as the sulforaphane or different phenolic compounds. On the other hand, some phytochemicals obtained positive results in clinical stages and were further approved for cancer treatment, such as vinca alkaloids or the paclitaxel. Nevertheless, these compounds are not exempt of limitations, such as low solubility, restricted effect on their own, negative side-effects, etc. This review aims to compile the information about the current phytochemicals used for cancer treatment and also promising candidates, main action mechanisms and also reported limitations. In this sense, some strategies to face the limitations have been considered, such as nano-based formulations to improve solubility or chemical modification to reduce toxicity. In conclusion, although more research is still necessary to develop more efficient and safe phytochemical drugs, more of these compounds might be used in future cancer therapies.
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Affiliation(s)
- Paula Garcia-Oliveira
- Nutrition and Bromatology Group, Analytical and Food Chemistry Department, Faculty of Food Science and Technology, University of Vigo, Ourense Campus, E-32004 Ourense, Spain; (P.G.-O.); (P.O.); (A.G.P.); (F.C.); (M.C.); (J.E.); (M.F.-C.)
- Centro de Investigação de Montanha (CIMO), Campus de Santa Apolonia, Instituto Politécnico de Bragança, 5300-253 Bragança, Portugal
| | - Paz Otero
- Nutrition and Bromatology Group, Analytical and Food Chemistry Department, Faculty of Food Science and Technology, University of Vigo, Ourense Campus, E-32004 Ourense, Spain; (P.G.-O.); (P.O.); (A.G.P.); (F.C.); (M.C.); (J.E.); (M.F.-C.)
| | - Antia Gonzalez Pereira
- Nutrition and Bromatology Group, Analytical and Food Chemistry Department, Faculty of Food Science and Technology, University of Vigo, Ourense Campus, E-32004 Ourense, Spain; (P.G.-O.); (P.O.); (A.G.P.); (F.C.); (M.C.); (J.E.); (M.F.-C.)
- Centro de Investigação de Montanha (CIMO), Campus de Santa Apolonia, Instituto Politécnico de Bragança, 5300-253 Bragança, Portugal
| | - Franklin Chamorro
- Nutrition and Bromatology Group, Analytical and Food Chemistry Department, Faculty of Food Science and Technology, University of Vigo, Ourense Campus, E-32004 Ourense, Spain; (P.G.-O.); (P.O.); (A.G.P.); (F.C.); (M.C.); (J.E.); (M.F.-C.)
| | - Maria Carpena
- Nutrition and Bromatology Group, Analytical and Food Chemistry Department, Faculty of Food Science and Technology, University of Vigo, Ourense Campus, E-32004 Ourense, Spain; (P.G.-O.); (P.O.); (A.G.P.); (F.C.); (M.C.); (J.E.); (M.F.-C.)
| | - Javier Echave
- Nutrition and Bromatology Group, Analytical and Food Chemistry Department, Faculty of Food Science and Technology, University of Vigo, Ourense Campus, E-32004 Ourense, Spain; (P.G.-O.); (P.O.); (A.G.P.); (F.C.); (M.C.); (J.E.); (M.F.-C.)
| | - Maria Fraga-Corral
- Nutrition and Bromatology Group, Analytical and Food Chemistry Department, Faculty of Food Science and Technology, University of Vigo, Ourense Campus, E-32004 Ourense, Spain; (P.G.-O.); (P.O.); (A.G.P.); (F.C.); (M.C.); (J.E.); (M.F.-C.)
- Centro de Investigação de Montanha (CIMO), Campus de Santa Apolonia, Instituto Politécnico de Bragança, 5300-253 Bragança, Portugal
| | - Jesus Simal-Gandara
- Nutrition and Bromatology Group, Analytical and Food Chemistry Department, Faculty of Food Science and Technology, University of Vigo, Ourense Campus, E-32004 Ourense, Spain; (P.G.-O.); (P.O.); (A.G.P.); (F.C.); (M.C.); (J.E.); (M.F.-C.)
- Correspondence: (J.S.-G.); (M.A.P.)
| | - Miguel Angel Prieto
- Nutrition and Bromatology Group, Analytical and Food Chemistry Department, Faculty of Food Science and Technology, University of Vigo, Ourense Campus, E-32004 Ourense, Spain; (P.G.-O.); (P.O.); (A.G.P.); (F.C.); (M.C.); (J.E.); (M.F.-C.)
- Correspondence: (J.S.-G.); (M.A.P.)
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25
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Fan X, Xiao X, Mao X, Chen D, Yu B, Wang J, Yan H. Tea bioactive components prevent carcinogenesis via anti-pathogen, anti-inflammation, and cell survival pathways. IUBMB Life 2021; 73:328-340. [PMID: 33368980 DOI: 10.1002/iub.2445] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 11/27/2020] [Revised: 12/22/2020] [Accepted: 12/23/2020] [Indexed: 01/08/2023]
Abstract
Cancer seriously impairs human health and survival. Many perturbations, such as increased oxidative stress, pathogen infection, and inflammation, promote the accumulation of DNA mutations, and ultimately lead to carcinogenesis. Tea is one of the most highly consumed beverages worldwide and has been linked to improvements in human health. Tea contains many active components, including tea polyphenols, tea polysaccharides, L-theanine, tea pigments, and caffeine among other common components. Several studies have identified components in tea that can directly or indirectly reduce carcinogenesis with some being used in a clinical setting. Many previous studies, in vitro and in vivo, have focused on the mechanisms that functional components of tea utilized to protect against cancer. One particular mechanism that has been well described is an improvement in antioxidant capacity seen with tea consumption. However, other mechanisms, including anti-pathogen, anti-inflammation and alterations in cell survival pathways, are also involved. The current review focuses on these anti-cancer mechanisms. This will be beneficial for clinical utilization of tea components in preventing and treating cancer in the future.
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Affiliation(s)
- Xiangqi Fan
- Animal Nutrition Institute, Sichuan Agricultural University, Key Laboratory for Animal Disease-Resistance Nutrition of China Ministry of Education, Key Laboratory of Animal Disease-Resistant Nutrition and Feed of China Ministry of Agriculture and Rural Affairs, Key Laboratory of Animal Disease-Resistant Nutrition of Sichuan Province, Chengdu, China
| | - Xiangjun Xiao
- Animal Nutrition Institute, Sichuan Agricultural University, Key Laboratory for Animal Disease-Resistance Nutrition of China Ministry of Education, Key Laboratory of Animal Disease-Resistant Nutrition and Feed of China Ministry of Agriculture and Rural Affairs, Key Laboratory of Animal Disease-Resistant Nutrition of Sichuan Province, Chengdu, China
| | - Xiangbing Mao
- Animal Nutrition Institute, Sichuan Agricultural University, Key Laboratory for Animal Disease-Resistance Nutrition of China Ministry of Education, Key Laboratory of Animal Disease-Resistant Nutrition and Feed of China Ministry of Agriculture and Rural Affairs, Key Laboratory of Animal Disease-Resistant Nutrition of Sichuan Province, Chengdu, China
| | - Daiwen Chen
- Animal Nutrition Institute, Sichuan Agricultural University, Key Laboratory for Animal Disease-Resistance Nutrition of China Ministry of Education, Key Laboratory of Animal Disease-Resistant Nutrition and Feed of China Ministry of Agriculture and Rural Affairs, Key Laboratory of Animal Disease-Resistant Nutrition of Sichuan Province, Chengdu, China
| | - Bing Yu
- Animal Nutrition Institute, Sichuan Agricultural University, Key Laboratory for Animal Disease-Resistance Nutrition of China Ministry of Education, Key Laboratory of Animal Disease-Resistant Nutrition and Feed of China Ministry of Agriculture and Rural Affairs, Key Laboratory of Animal Disease-Resistant Nutrition of Sichuan Province, Chengdu, China
| | - Jianping Wang
- Animal Nutrition Institute, Sichuan Agricultural University, Key Laboratory for Animal Disease-Resistance Nutrition of China Ministry of Education, Key Laboratory of Animal Disease-Resistant Nutrition and Feed of China Ministry of Agriculture and Rural Affairs, Key Laboratory of Animal Disease-Resistant Nutrition of Sichuan Province, Chengdu, China
| | - Hui Yan
- Animal Nutrition Institute, Sichuan Agricultural University, Key Laboratory for Animal Disease-Resistance Nutrition of China Ministry of Education, Key Laboratory of Animal Disease-Resistant Nutrition and Feed of China Ministry of Agriculture and Rural Affairs, Key Laboratory of Animal Disease-Resistant Nutrition of Sichuan Province, Chengdu, China
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26
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Qiu YL, Zheng H, Devos A, Selby H, Gevaert O. A meta-learning approach for genomic survival analysis. Nat Commun 2020; 11:6350. [PMID: 33311484 PMCID: PMC7733508 DOI: 10.1038/s41467-020-20167-3] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 04/23/2020] [Accepted: 11/16/2020] [Indexed: 02/07/2023] Open
Abstract
RNA sequencing has emerged as a promising approach in cancer prognosis as sequencing data becomes more easily and affordably accessible. However, it remains challenging to build good predictive models especially when the sample size is limited and the number of features is high, which is a common situation in biomedical settings. To address these limitations, we propose a meta-learning framework based on neural networks for survival analysis and evaluate it in a genomic cancer research setting. We demonstrate that, compared to regular transfer-learning, meta-learning is a significantly more effective paradigm to leverage high-dimensional data that is relevant but not directly related to the problem of interest. Specifically, meta-learning explicitly constructs a model, from abundant data of relevant tasks, to learn a new task with few samples effectively. For the application of predicting cancer survival outcome, we also show that the meta-learning framework with a few samples is able to achieve competitive performance with learning from scratch with a significantly larger number of samples. Finally, we demonstrate that the meta-learning model implicitly prioritizes genes based on their contribution to survival prediction and allows us to identify important pathways in cancer.
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Affiliation(s)
- Yeping Lina Qiu
- Department of Electrical Engineering, Stanford University, Stanford, USA
- Department of Medicine, Stanford Center for Biomedical Informatics Research, Stanford University, Stanford, USA
| | - Hong Zheng
- Department of Medicine, Stanford Center for Biomedical Informatics Research, Stanford University, Stanford, USA
| | - Arnout Devos
- School of Computer and Communication Sciences, Swiss Federal Institute of Technology Lausanne (EPFL), Lausanne, Switzerland
| | - Heather Selby
- Department of Medicine, Stanford Center for Biomedical Informatics Research, Stanford University, Stanford, USA
| | - Olivier Gevaert
- Department of Medicine, Stanford Center for Biomedical Informatics Research, Stanford University, Stanford, USA.
- Department of Biomedical Data Science, Stanford University, Stanford, USA.
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27
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Massimino L, Lovisa S, Antonio Lamparelli L, Danese S, Ungaro F. Gut eukaryotic virome in colorectal carcinogenesis: Is that a trigger? Comput Struct Biotechnol J 2020; 19:16-28. [PMID: 33363706 PMCID: PMC7750180 DOI: 10.1016/j.csbj.2020.11.055] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 09/30/2020] [Revised: 11/24/2020] [Accepted: 11/28/2020] [Indexed: 02/07/2023] Open
Abstract
The human gut microbiota is composed of bacteria and viruses that might be associated with colorectal cancer (CRC) onset and progression. Indeed, although viral infections have been reported to be the primary trigger in many diseases, the role of eukaryotic viruses populating the gut mucosa during early colorectal carcinogenesis is underinvestigated. Human eukaryotic viruses in the gut were found to induce alterations of the immune homeostasis so that some viral-dependent mechanisms likely able to induce DNA alterations in the bowel wall have been proposed, although no demonstration is available yet. However, thanks to the latest advancements in computational biology and the implementation of the bioinformatic pipelines, the option of establishing a direct causative link between intestinal virome and CRC will be possible soon, hopefully paving the way to innovative therapeutic strategies blocking or reverting the CRC pathogenesis.
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Affiliation(s)
- Luca Massimino
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Milan, Italy
| | - Sara Lovisa
- IBD Center, Laboratory of Gastrointestinal Immunopathology, Humanitas Clinical and Research Center, Rozzano, Milan, Italy
| | | | - Silvio Danese
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Milan, Italy
- IBD Center, Laboratory of Gastrointestinal Immunopathology, Humanitas Clinical and Research Center, Rozzano, Milan, Italy
| | - Federica Ungaro
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Milan, Italy
- IBD Center, Laboratory of Gastrointestinal Immunopathology, Humanitas Clinical and Research Center, Rozzano, Milan, Italy
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Abstract
Mass spectrometry imaging (MSI) is a label-free molecular imaging technique allowing an untargeted detection of a broad range of biomolecules and xenobiotics. MSI enables imaging of the spatial distribution of proteins, peptides, lipids and metabolites from a wide range of samples. To date, this technique is commonly applied to tissue sections in cancer diagnostics and biomarker development, but also molecular histology in general. Advances in the methodology and bioinformatics improved the resolution of MS images below the single cell level and increased the flexibility of the workflow. However, MSI-based research in virology is just starting to gain momentum and its full potential has not been exploited yet. In this review, we discuss the main applications of MSI in virology. We review important aspects of matrix-assisted laser desorption/ionization (MALDI) MSI, the most widely used MSI technique in virology. In addition, we summarize relevant literature on MSI studies that aim to unravel virus-host interactions and virus pathogenesis, to elucidate antiviral drug kinetics and to improve current viral disease diagnostics. Collectively, these studies strongly improve our general understanding of virus-induced changes in the proteome, metabolome and metabolite distribution in host tissues of humans, animals and plants upon infection. Furthermore, latest MSI research provided important insights into the drug distribution and distribution kinetics, especially in antiretroviral research. Finally, MSI-based investigations of oncogenic viruses greatly increased our knowledge on tumor mass signatures and facilitated the identification of cancer biomarkers.
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Affiliation(s)
- Luca D Bertzbach
- Institute of Virology, Freie Universität Berlin, Berlin, Germany
| | | | - Axel Karger
- Institute of Molecular Virology and Cell Biology, Friedrich-Loeffler-Institut, Greifswald-Insel Riems, Germany.
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El-Qushayri AE, Ghozy S, Morsy S, Ali F, Islam SMS. Blood Transfusion and the Risk of Cancer in the US Population: Is There an Association? Clin Epidemiol 2020; 12:1121-1127. [PMID: 33116905 PMCID: PMC7573206 DOI: 10.2147/clep.s271275] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 07/08/2020] [Accepted: 09/08/2020] [Indexed: 12/15/2022] Open
Abstract
Purpose We aimed to test if blood transfusion is a risk factor for the prevalence of cancer. Patients and Methods We conducted secondary analyses using the NHANES database from 1999 to 2016. We included all individuals who received a blood transfusion with known cancer comorbidity (diseased or not). We used univariate logistic regression to identify any possible association between history of blood transfusion and the prevalence of cancer with adjustment for different co-founders was done. Regression results were expressed as odds ratios (ORs) and 95% confidence interval (95% CI) for both adjusted and unadjusted models. Results A total of 48,796 individuals were included in the final analysis: 6333 of them received a blood transfusion, while the other 42,463 individuals did not. In individuals who received a blood transfusion, the most prevalent cancer was breast cancer (3.4%), followed by prostate (3.0%), non-melanoma skin (2.4%) cancers, while non-melanoma skin (1.2%), prostate (1.1%) and breast (1.1%) cancers were the most prevalent in the no transfusion individuals. There was a significant association between the reported history of blood transfusion and the overall prevalence of cancer in both the unadjusted (OR= 3.47; 95% CI= 3.23–0.72; P-value< 0.001) and adjusted model (OR= 1.86; 95% CI= 1.72–0.2.01; P-value< 0.001). On the level of individual cancers, a significant reduction in cancer prevalence was found in patients with breast, cervix, larynx, Hodgkin’s lymphoma, melanoma, prostate, skin (non-melanoma), skin (unspecified), soft tissue, testicular, thyroid, and uterine cancers. Conclusion Results did not imply any concrete association between cancer risk and history of blood transfusion. These findings would help in debunking the myth of increased cancer risk following blood transfusion.
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Affiliation(s)
| | - Sherief Ghozy
- Faculty of Medicine, Mansoura University, Mansoura, Egypt
| | - Sara Morsy
- Medical Biochemistry and Molecular Biology Department, Faculty of Medicine, Tanta University, Tanta, Egypt
| | - Faria Ali
- Department of Internal Medicine, Henry Ford Allegiance Health, Jackson, MI 49201, USA
| | - Sheikh Mohammed Shariful Islam
- Institute for Physical Activity and Nutrition (IPAN), School of Exercise and Nutrition Sciences, Deakin University, Melbourne, Australia
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30
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Kerr MD, McBride DA, Chumber AK, Shah NJ. Combining therapeutic vaccines with chemo- and immunotherapies in the treatment of cancer. Expert Opin Drug Discov 2020; 16:89-99. [PMID: 32867561 DOI: 10.1080/17460441.2020.1811673] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Indexed: 12/14/2022]
Abstract
INTRODUCTION Breakthroughs in cancer immunotherapy have spurred interest in the development of vaccines to mediate prophylactic protection and therapeutic efficacy against primary tumors or to prevent relapse. However, immunosuppressive mechanisms employed by cancer cells to generate effective resistance have hampered clinical translation of therapeutic cancer vaccines. To enhance vaccine efficacy, the immunomodulatory properties of cytoreductive therapies could amplify a cancer-specific immune response. AREAS COVERED Herein, the authors discuss therapeutic cancer vaccines that harness whole cells and antigen-targeted vaccines. First, recent advancements in both autologous and allogeneic whole-cell vaccines and combinations with checkpoint blockade and chemotherapy are reviewed. Next, tumor antigen-targeted vaccines using peptide-based vaccines and DNA-vaccines are discussed. Finally, combination therapies using antigen-targeted vaccines are reviewed. EXPERT OPINION A deeper understanding of the immunostimulatory properties of cytoreductive therapies has supported their utility in combination therapies involving cancer vaccines as a potential strategy to induce a durable anti-tumor immune response for multiple types of cancers. Based on current evidence, combination therapies may have synergies that depend on the identity of the cytotoxic agent, vaccine target, dosing schedule, and cancer type. Together, these observations suggest that combining cancer vaccines with immunomodulatory cytoreductive therapy is a promising strategy for cancer therapy.
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Affiliation(s)
- Matthew D Kerr
- Department of NanoEngineering, University of California , San Diego, CA, USA.,Program in Chemical Engineering, University of California , San Diego, CA, USA.,Center for Nano-Immuno Engineering, University of California , San Diego, CA, USA
| | - David A McBride
- Department of NanoEngineering, University of California , San Diego, CA, USA.,Program in Chemical Engineering, University of California , San Diego, CA, USA.,Center for Nano-Immuno Engineering, University of California , San Diego, CA, USA
| | - Arun K Chumber
- Department of NanoEngineering, University of California , San Diego, CA, USA.,Program in Chemical Engineering, University of California , San Diego, CA, USA.,Center for Nano-Immuno Engineering, University of California , San Diego, CA, USA
| | - Nisarg J Shah
- Department of NanoEngineering, University of California , San Diego, CA, USA.,Program in Chemical Engineering, University of California , San Diego, CA, USA.,Center for Nano-Immuno Engineering, University of California , San Diego, CA, USA.,Program in Immunology, University of California , San Diego, CA, USA.,San Diego Center for Precision Immunotherapy, Moores Cancer Center, University of California , San Diego, CA, USA
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31
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Gock M, Kordt M, Matschos S, Mullins CS, Linnebacher M. Patient-individual cancer cell lines and tissue analysis delivers no evidence of sequences from DNA viruses in colorectal cancer cells. BMC Gastroenterol 2020; 20:260. [PMID: 32762707 PMCID: PMC7409650 DOI: 10.1186/s12876-020-01404-x] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Academic Contribution Register] [Received: 07/28/2019] [Accepted: 07/28/2020] [Indexed: 12/15/2022] Open
Abstract
Background Several DNA viruses are highly suspicious to have oncogenic effects in humans. This study investigates the presence of potentially oncogenic viruses such as SV40, JCV, BKV and EBV in patient-derived colorectal carcinoma (CRC) cells typifying all molecular subtypes of CRC. Methods Sample material (gDNA and cDNA) of a total of 49 patient-individual CRC cell lines and corresponding primary material from 11 patients, including normal, tumor-derived and metastasis-derived tissue were analyzed for sequences of SV40, JVC, BKV and EBV using endpoint PCR. In addition, the susceptibility of CRC cells to JCV and BKV was examined using a long-term cultivation approach of patient-individual cells in the presence of viruses. Results No virus-specific sequences could be detected in all specimens. Likewise, no morphological changes were observed and no evidence for viral infection or integration could be provided after long term CRC cell cultivation in presence of viral particles. Conclusions In summary, the presented data suggest that there is no direct correlation between tumorigenesis and viral load and consequently no evidence for a functional role of the DNA viruses included into this analysis in CRC development.
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Affiliation(s)
- Michael Gock
- Department of General Surgery, University of Rostock, Rostock, Germany
| | - Marcel Kordt
- Department of General Surgery, Molecular Oncology and Immunotherapy, University of Rostock, Schillingallee 35, D-18057, Rostock, Germany
| | - Stephanie Matschos
- Department of General Surgery, Molecular Oncology and Immunotherapy, University of Rostock, Schillingallee 35, D-18057, Rostock, Germany
| | - Christina S Mullins
- Department of General Surgery, Molecular Oncology and Immunotherapy, University of Rostock, Schillingallee 35, D-18057, Rostock, Germany
| | - Michael Linnebacher
- Department of General Surgery, Molecular Oncology and Immunotherapy, University of Rostock, Schillingallee 35, D-18057, Rostock, Germany.
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32
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Kakabadze MZ, Paresishvili T, Karalashvili L, Chakhunashvili D, Kakabadze Z. Oral microbiota and oral cancer: Review. Oncol Rev 2020; 14:476. [PMID: 32676172 PMCID: PMC7358985 DOI: 10.4081/oncol.2020.476] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 01/22/2020] [Accepted: 05/15/2020] [Indexed: 12/23/2022] Open
Abstract
In this review, we draw attention and discuss the risk factors and causes of the development of oral squamous cell carcinoma (OSCC) focusing on oral microbiota. Recently, a breakthrough in the study of cancer has been the discovery of the relationship between the presence of certain types of bacteria and the development of cancer in the human body. Studies have shown that, Porphyromonas gingivalis (P. gingivalis) bacteria that is responsible for the destructive processes in the oral cavity, could play an important role in the development of OSCC. In our continuing search for bacteria that causes oral squamous cell carcinoma, we came across the Pseudomona aeruginosa, which due to its metabolite properties, may play important role in carcinogenesis of oral cancer. One possible mechanism is the ability of Pseudomonas to synthesize nitric oxide (NO) that modulates different cancer-related appearances such as apoptosis, cell cycle, angiogenesis, invasion, and metastasis. We think that P. aeruginosa increases the concentration of NO by converting salivary nitrite to nitric oxide, and this is how it contributes to NO-related carcinogenesis. Early diagnosis and treatment of periodontitis are very important not only for patients' oral health, but also for the prevention of OSCC development. Screening test for OSCC based on determination of salivary NO levels could be appealing and may prove to be useful assay for diagnosis and early detection of disease progression in oral cancer.
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Affiliation(s)
| | | | - Lia Karalashvili
- Ivane Javakhishvili Tbilisi State University
- Tbilisi State Medical University, Tbilisi, Georgia
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33
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Human DNA tumor viruses and oncogenesis. Anim Biotechnol 2020. [PMCID: PMC7329114 DOI: 10.1016/b978-0-12-811710-1.00007-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Indexed: 11/16/2022]
Abstract
DNA tumor viruses induce tumors in animals and humans by transforming the infected host cells. These oncogenic viruses encode viral proteins, which deregulate the integrated framework of host cellular processes, while preventing cell death. Studies revealed newer insights as to how specific tumor targets could be modulated for tumor therapy.
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34
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Suares A, Tapia C, González-Pardo V. VDR agonists down regulate PI3K/Akt/mTOR axis and trigger autophagy in Kaposi's sarcoma cells. Heliyon 2019; 5:e02367. [PMID: 31497671 PMCID: PMC6722267 DOI: 10.1016/j.heliyon.2019.e02367] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 03/07/2019] [Revised: 05/14/2019] [Accepted: 08/21/2019] [Indexed: 12/21/2022] Open
Abstract
The Kaposi's sarcoma-associated herpesvirus G protein-coupled receptor (KSHV/vGPCR) is a key molecule in the pathogenesis of Kaposi's sarcoma. We have previously shown that 1α,25(OH)2D3 or its less-calcemic analog TX 527 inhibits the proliferation of endothelial cells expressing vGPCR, NF-κB activity and induces apoptosis in a VDR dependent manner. In this work, we further explored whether 1α,25(OH)2D3 or TX 527 regulates PI3K/Akt/mTOR axis and induces autophagy as part of its antineoplastic mechanism of action. Proliferation assays indicated that vGPCR cell number decreased in presence of LY294002 (PI3K/Akt inhibitor) likewise 1α,25(OH)2D3 or TX 527 (10 nM, 48 h). Also, Akt phosphorylation was found decreased in dose (0.1-100 nM) and time response studies (12-72 h) after both compounds treatments. In addition, decreased phosphorylated Akt was significantly observed in the nucleus. Moreover, regulation of Akt phosphorylation was NF-κB and VDR dependent. TNFAIP3/A20, an ubiquitin-editing enzyme, a direct NF-κB target gene and a negative regulator of Beclin-1, was down-regulated whereas Beclin-1 was up-regulated after 10 nM of 1α,25(OH)2D3 or TX 527 treatment. Decrement in Akt phosphorylation was accompanied by a reduced mTOR phosphorylation and an increase in the autophagy marker LC3-II. Since increment in autophagosomes not always indicates increment in autophagy activity, we used Chloroquine (CQ, 1 μM), an inhibitor of autophagy flow, to confirm autophagy after both VDR agonists treatment. In conclusion, VDR agonists, 1α,25(OH)2D3 or TX 527, inhibited PI3K/Akt/mTOR axis and induced autophagy in endothelial cells expressing vGPCR by a VDR-dependent mechanism.
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Affiliation(s)
- Alejandra Suares
- Instituto de Ciencias Biológicas y Biomédicas del Sur (INBIOSUR), Departamento de Biología Bioquímica y Farmacia, Universidad Nacional del Sur (UNS)-CONICET, San Juan 670, 8000, Bahía Blanca, Argentina
- IFIBYNE – Instituto de Fisiología, Biología Molecular y Neurociencias (UBA-CONICET), Ciudad Universitaria, 1428, Ciudad Autónoma de Buenos Aires, Argentina
| | - Cinthya Tapia
- Instituto de Ciencias Biológicas y Biomédicas del Sur (INBIOSUR), Departamento de Biología Bioquímica y Farmacia, Universidad Nacional del Sur (UNS)-CONICET, San Juan 670, 8000, Bahía Blanca, Argentina
| | - Verónica González-Pardo
- Instituto de Ciencias Biológicas y Biomédicas del Sur (INBIOSUR), Departamento de Biología Bioquímica y Farmacia, Universidad Nacional del Sur (UNS)-CONICET, San Juan 670, 8000, Bahía Blanca, Argentina
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35
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Yuan X, Liu Y, Li G, Lan Z, Ma M, Li H, Kong J, Sun J, Hou G, Hou X, Ma Y, Ren F, Zhou F, Gao S. Blockade of Immune-Checkpoint B7-H4 and Lysine Demethylase 5B in Esophageal Squamous Cell Carcinoma Confers Protective Immunity against P. gingivalis Infection. Cancer Immunol Res 2019; 7:1440-1456. [PMID: 31350278 DOI: 10.1158/2326-6066.cir-18-0709] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 10/05/2018] [Revised: 02/14/2019] [Accepted: 07/22/2019] [Indexed: 11/16/2022]
Abstract
Pathogens are capable of hijacking immune defense mechanisms, thereby creating a tolerogenic environment for hypermutated malignant cells that arise within the site of infection. Immune checkpoint-oriented immunotherapies have shown considerable promise. Equally important, the epigenetic reprogramming of an immune-evasive phenotype that activates the immune system in a synergistic manner can improve immunotherapy outcomes. These advances have led to combinations of epigenetic- and immune-based therapeutics. We previously demonstrated that Porphyromonas gingivalis isolated from esophageal squamous cell carcinoma (ESCC) lesions represents a major pathogen associated with this deadly disease. In this study, we examined the mechanisms associated with host immunity during P. gingivalis infection and demonstrated that experimentally infected ESCC responds by increasing the expression of B7-H4 and lysine demethylase 5B, which allowed subsequent in vivo analysis of the immunotherapeutic effects of anti-B7-H4 and histone demethylase inhibitors in models of chronic infection and immunity against xenografted human tumors. Using three different preclinical mouse models receiving combined therapy, we showed that mice mounted strong resistance against P. gingivalis infection and tumor challenge. This may have occurred via generation of a T cell-mediated response in the microenvironment and formation of immune memory. In ESCC subjects, coexpression of B7-H4 and KDM5B correlated more significantly with bacterial load than with the expression of either molecule alone. These results highlight the unique ability of P. gingivalis to evade immunity and define potential targets that can be exploited therapeutically to improve the control of P. gingivalis infection and the development of associated neoplasia.
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Affiliation(s)
- Xiang Yuan
- Henan Key Laboratory of Cancer Epigenetics, Cancer Hospital, The First Affiliated Hospital, College of Clinical Medicine, Medical College of Henan University of Science and Technology, Luoyang, China.,Department of Medical Oncology, Cancer Hospital, The First Affiliated Hospital, College of Clinical Medicine, Medical College of Henan University of Science and Technology, Luoyang, China
| | - Yiwen Liu
- Henan Key Laboratory of Cancer Epigenetics, Cancer Hospital, The First Affiliated Hospital, College of Clinical Medicine, Medical College of Henan University of Science and Technology, Luoyang, China
| | - Guifang Li
- Department of Pulmonary Tumor Surgery, Cancer Hospital, The First Affiliated Hospital, College of Clinical Medicine, Medical College of Henan University of Science and Technology, Luoyang, China
| | - Zijun Lan
- Henan Key Laboratory of Cancer Epigenetics, Cancer Hospital, The First Affiliated Hospital, College of Clinical Medicine, Medical College of Henan University of Science and Technology, Luoyang, China
| | - Mingyang Ma
- Department of Pulmonary Tumor Surgery, Cancer Hospital, The First Affiliated Hospital, College of Clinical Medicine, Medical College of Henan University of Science and Technology, Luoyang, China
| | - Huaxu Li
- Queen Mary College, Medical College of Nanchang University, Nanchang, China
| | - Jinyu Kong
- Henan Key Laboratory of Cancer Epigenetics, Cancer Hospital, The First Affiliated Hospital, College of Clinical Medicine, Medical College of Henan University of Science and Technology, Luoyang, China
| | - Jiangtao Sun
- Department of Pulmonary Tumor Surgery, Cancer Hospital, The First Affiliated Hospital, College of Clinical Medicine, Medical College of Henan University of Science and Technology, Luoyang, China
| | - Gaochao Hou
- Henan Key Laboratory of Cancer Epigenetics, Cancer Hospital, The First Affiliated Hospital, College of Clinical Medicine, Medical College of Henan University of Science and Technology, Luoyang, China
| | - Xurong Hou
- Department of Medical Oncology, Cancer Hospital, The First Affiliated Hospital, College of Clinical Medicine, Medical College of Henan University of Science and Technology, Luoyang, China
| | - Yingjian Ma
- Henan Key Laboratory of Cancer Epigenetics, Cancer Hospital, The First Affiliated Hospital, College of Clinical Medicine, Medical College of Henan University of Science and Technology, Luoyang, China
| | - Feng Ren
- Department of Pathology, Xinxiang Medical University, Xinxiang, China
| | - Fuyou Zhou
- Department of Thoracic Surgery, Anyang Tumor Hospital, Anyang, Henan, China.
| | - Shegan Gao
- Henan Key Laboratory of Cancer Epigenetics, Cancer Hospital, The First Affiliated Hospital, College of Clinical Medicine, Medical College of Henan University of Science and Technology, Luoyang, China. .,Department of Medical Oncology, Cancer Hospital, The First Affiliated Hospital, College of Clinical Medicine, Medical College of Henan University of Science and Technology, Luoyang, China
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36
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Suares A, Tapia C, González-Pardo V. Antineoplastic effect of 1α,25(OH) 2D 3 in spheroids from endothelial cells transformed by Kaposi's sarcoma-associated herpesvirus G protein coupled receptor. J Steroid Biochem Mol Biol 2019; 186:122-129. [PMID: 30308321 DOI: 10.1016/j.jsbmb.2018.10.004] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Academic Contribution Register] [Received: 08/25/2018] [Revised: 09/27/2018] [Accepted: 10/06/2018] [Indexed: 12/24/2022]
Abstract
The Kaposi's sarcoma-associated herpesvirus G protein-coupled receptor (KSHV/vGPCR) is a key molecule in the pathogenesis of Kaposi's sarcoma. In endothelial cells, tumor maintenance and NF-κB activation depends on vGPCR constitutive expression and activity. We have previously demonstrated that 1α,25(OH)2D3 induces apoptosis in a VDR dependent manner, inhibits vGPCR cell growth and NF-κB activity. In this study, we developed a method to obtain multicellular spheroids (MCS) from endothelial cells expressing vGPCR in order to test whether MCS have a similar response to 2D-cultures after 1α,25(OH)2D3 treatment. Firstly, we found that vGPCR MCS started to form at 2nd day-growth, reaching a diameter up to 300 μm at 7th day-growth, whereas cells without vGPCR expression (SVEC) developed spheroids earlier and remained smaller throughout the period monitored. Secondly, vGPCR MCS size and architecture were analyzed during 1α,25(OH)2D3 (0.1-100 nM, 48 h) treatment. We found that once treated with 10 nM of 1α,25(OH)2D3 the initials MCS began a slight disaggregation with no changes in size; whereas at the higher dose (100 nM) the architecture of MCS was found completely broken. Furthermore, VDR mRNA expression increased significantly and this change was accompanied by a reduction of HIF-1α, an increase of VEGF, p21 and Bim mRNA expression. Finally, results from Western blot analysis showed that 1α,25(OH)2D3 decreased Akt and ERK1/2 protein phosphorylation. In conclusion, these data have revealed that 1α,25(OH)2D3 inhibits vGPCR MCS proliferation and induces apoptosis similar to vGPCR cells growing in 2D-cultures.
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Affiliation(s)
- Alejandra Suares
- Instituto de Ciencias Biológicas y Biomédicas del Sur (INBIOSUR), Departamento de Biología Bioquímica y Farmacia, Universidad Nacional del Sur (UNS)-CONICET, San Juan 670, 8000 Bahía Blanca, Argentina
| | - Cinthya Tapia
- Instituto de Ciencias Biológicas y Biomédicas del Sur (INBIOSUR), Departamento de Biología Bioquímica y Farmacia, Universidad Nacional del Sur (UNS)-CONICET, San Juan 670, 8000 Bahía Blanca, Argentina
| | - Verónica González-Pardo
- Instituto de Ciencias Biológicas y Biomédicas del Sur (INBIOSUR), Departamento de Biología Bioquímica y Farmacia, Universidad Nacional del Sur (UNS)-CONICET, San Juan 670, 8000 Bahía Blanca, Argentina.
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37
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Red blood cell transfusion and its alternatives in oncologic surgery-A critical evaluation. Crit Rev Oncol Hematol 2018; 134:1-9. [PMID: 30771868 DOI: 10.1016/j.critrevonc.2018.11.011] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 08/28/2018] [Revised: 10/14/2018] [Accepted: 11/29/2018] [Indexed: 01/28/2023] Open
Abstract
Although blood transfusions have been used for more than 100 years and their potential to save lives is indisputable, there is still limited data on medium- and long-term outcomes after hemotherapy. Until recently, red blood cell transfusions represented the most commonly employed treatment for cancer anemia. As transfusions have been related to worse patient outcome in oncologic surgery, preventive strategies and alternative treatment approaches in the perioperative setting are warranted. This review aims to evaluate the evidence concerning the impact of transfusion on the course of malignant diseases with a focus on oncologic surgery and to provide a bundle of measures to improve patient care. The perioperative period is pivotal in determining long-term cancer outcome. An increasingly recognized area for improvement during this highly sensitive period is the treatment of anemia for three main reasons: Firstly, anemia has been recognized as an independent predictor of poor prognosis in cancer patients. Secondly, anemia is largely undertreated. Thirdly and probably most importantly, anemia therapy relied and often still relies heavily on red blood cell (RBC) transfusions, which may be an often suboptimal stopgap treatment. Perioperative RBC transfusions should be kept to a minimum due to growing concerns regarding the associated risks, which this review tries to clarify by providing an update of recent literature. This review furthermore discusses treatments for anemia and provides best-practice approaches to improve perioperative management of oncology patients undergoing surgery.
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38
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Wyczalkowski MA, Wylie KM, Cao S, McLellan MD, Flynn J, Huang M, Ye K, Fan X, Chen K, Wendl MC, Ding L. BreakPoint Surveyor: a pipeline for structural variant visualization. Bioinformatics 2018; 33:3121-3122. [PMID: 28582538 DOI: 10.1093/bioinformatics/btx362] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 01/30/2017] [Accepted: 06/01/2017] [Indexed: 11/14/2022] Open
Abstract
Summary BreakPoint Surveyor (BPS) is a computational pipeline for the discovery, characterization, and visualization of complex genomic rearrangements, such as viral genome integration, in paired-end sequence data. BPS facilitates interpretation of structural variants by merging structural variant breakpoint predictions, gene exon structure, read depth, and RNA-sequencing expression into a single comprehensive figure. Availability and implementation Source code and sample data freely available for download at https://github.com/ding-lab/BreakPointSurveyor, distributed under the GNU GPLv3 license, implemented in R, Python and BASH scripts, and supported on Unix/Linux/OS X operating systems. Contact lding@wustl.edu. Supplementary information Supplementary data are available at Bioinformatics online.
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Affiliation(s)
| | | | - Song Cao
- Oncology Division, Department of Medicine.,McDonnell Genome Institute
| | | | | | - Mo Huang
- Oncology Division, Department of Medicine.,McDonnell Genome Institute
| | - Kai Ye
- McDonnell Genome Institute
| | - Xian Fan
- Department of Bioinformatics and Computational Biology, University of Texas MD Anderson Cancer Center, Houston, TX 77230, USA
| | - Ken Chen
- Department of Bioinformatics and Computational Biology, University of Texas MD Anderson Cancer Center, Houston, TX 77230, USA
| | - Michael C Wendl
- Oncology Division, Department of Medicine.,McDonnell Genome Institute.,Department of Genetics.,Department of Mathematics, Washington University in St. Louis, St. Louis, MO 63108, USA
| | - Li Ding
- Oncology Division, Department of Medicine.,McDonnell Genome Institute.,Department of Genetics.,Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO 63110, USA
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39
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Hussein HAM, Okafor IB, Walker LR, Abdel-Raouf UM, Akula SM. Cellular and viral oncogenes: the key to unlocking unknowns of Kaposi's sarcoma-associated herpesvirus pathogenesis. Arch Virol 2018; 163:2633-2643. [PMID: 29936609 DOI: 10.1007/s00705-018-3918-3] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 01/17/2018] [Accepted: 06/08/2018] [Indexed: 02/06/2023]
Abstract
Oncogenic viruses carry an extensive arsenal of oncogenes for hijacking cellular pathways. Notably, variations in oncogenes among tumor-producing viruses give rise to different mechanisms for cellular transformation. Specifically, Kaposi's sarcoma-associated herpesvirus (KSHV) is an oncogenic virus able to infect and transform a variety of cell types. The oncogenicity of KSHV disseminates from the virus' ability to induce and encode a wide variety of both cellular and viral oncogenes. Such an array of cellular and viral oncogenes enables KSHV to induce the malignant phenotype of a KSHV-associated cancer. Evolutionarily, KSHV has acquired many oncogenic homologues capable of inducing cell proliferation, cell differentiation, cell survival, and immune evasion. Integration between inducing and encoding oncogenes plays a vital role in KSHV pathogenicity. KSHV is alleged to harbor the highest number of potential oncogenes by which a virus promotes cellular transformation and malignancy. Many KSHV inducing/encoding oncogenes are mainly expressed during the latent phase of KSHV infection, a period required for virus establishment of malignant cellular transformation. Elucidation of the exact mechanism(s) by which oncogenes promote KSHV pathogenicity would not only give rise to potential novel therapeutic targets/drugs but would also add to our understanding of cancer biology. The scope of this review is to examine the roles of the most important cellular and viral oncogenes involved in KSHV pathogenicity.
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Affiliation(s)
- Hosni A M Hussein
- Department of Microbiology and Immunology, Brody School of Medicine at East Carolina University, Greenville, NC, 27834, USA
| | - Ikenna B Okafor
- Department of Microbiology and Immunology, Brody School of Medicine at East Carolina University, Greenville, NC, 27834, USA
| | - Lia R Walker
- Department of Microbiology and Immunology, Brody School of Medicine at East Carolina University, Greenville, NC, 27834, USA
| | - Usama M Abdel-Raouf
- Faculty of Science, Al Azhar University, Assiut Branch, Assiut, 71524, Egypt
| | - Shaw M Akula
- Department of Microbiology and Immunology, Brody School of Medicine at East Carolina University, Greenville, NC, 27834, USA.
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40
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Vranic S, Cyprian FS, Akhtar S, Al Moustafa AE. The Role of Epstein-Barr Virus in Cervical Cancer: A Brief Update. Front Oncol 2018; 8:113. [PMID: 29719817 PMCID: PMC5913353 DOI: 10.3389/fonc.2018.00113] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 02/09/2018] [Accepted: 03/29/2018] [Indexed: 12/19/2022] Open
Abstract
Epstein–Barr virus (EBV) belongs to the group of gamma-herpes viruses and was the first recognized human oncovirus. EBV is responsible for infectious mononucleosis and multiple lymphoid and epithelial malignancies including B-cell lymphomas (Burkitt lymphoma, Hodgkin lymphoma, and post-transplant lymphoproliferative disorder), various T-cell/NK lymphoproliferative disorders, nasopharyngeal carcinoma, and gastric carcinoma, respectively. In addition, the presence of EBV has been documented in other cancers including breast, prostate, oral, and salivary gland carcinomas. The presence and role of EBV in cervical cancer and its precursor lesions (CIN) have also been described, but the results from the literature are inconsistent, and the causal role of EBV in cervical cancer pathogenesis has not been established yet. In the present review, we briefly surveyed and critically appraised the current literature on EBV in cervical cancer and its variants (lymphoepithelioma-like carcinoma) as well as its precursor lesions (CIN). In addition, we discussed the possible interactions between EBV and human papilloma virus as well as between EBV and immune checkpoint regulators (PD-L1). Though further studies are needed, the available data suggest a possible causal relationship between EBV and cervical cancer pathogenesis.
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Affiliation(s)
- Semir Vranic
- College of Medicine, Qatar University, Doha, Qatar
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41
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Schuh A, Dreau H, Knight SJL, Ridout K, Mizani T, Vavoulis D, Colling R, Antoniou P, Kvikstad EM, Pentony MM, Hamblin A, Protheroe A, Parton M, Shah KA, Orosz Z, Athanasou N, Hassan B, Flanagan AM, Ahmed A, Winter S, Harris A, Tomlinson I, Popitsch N, Church D, Taylor JC. Clinically actionable mutation profiles in patients with cancer identified by whole-genome sequencing. Cold Spring Harb Mol Case Stud 2018; 4:a002279. [PMID: 29610388 PMCID: PMC5880257 DOI: 10.1101/mcs.a002279] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 08/30/2017] [Accepted: 02/09/2018] [Indexed: 02/07/2023] Open
Abstract
Next-generation sequencing (NGS) efforts have established catalogs of mutations relevant to cancer development. However, the clinical utility of this information remains largely unexplored. Here, we present the results of the first eight patients recruited into a clinical whole-genome sequencing (WGS) program in the United Kingdom. We performed PCR-free WGS of fresh frozen tumors and germline DNA at 75× and 30×, respectively, using the HiSeq2500 HTv4. Subtracted tumor VCFs and paired germlines were subjected to comprehensive analysis of coding and noncoding regions, integration of germline with somatically acquired variants, and global mutation signatures and pathway analyses. Results were classified into tiers and presented to a multidisciplinary tumor board. WGS results helped to clarify an uncertain histopathological diagnosis in one case, led to informed or supported prognosis in two cases, leading to de-escalation of therapy in one, and indicated potential treatments in all eight. Overall 26 different tier 1 potentially clinically actionable findings were identified using WGS compared with six SNVs/indels using routine targeted NGS. These initial results demonstrate the potential of WGS to inform future diagnosis, prognosis, and treatment choice in cancer and justify the systematic evaluation of the clinical utility of WGS in larger cohorts of patients with cancer.
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Affiliation(s)
- Anna Schuh
- Oxford Molecular Diagnostics Centre, Department of Oncology, University of Oxford, Oxford OX3 9DU, United Kingdom
- Oxford NIHR Biomedical Research Centre, Oxford OX4 2PG, United Kingdom
| | - Helene Dreau
- Oxford Molecular Diagnostics Centre, Department of Oncology, University of Oxford, Oxford OX3 9DU, United Kingdom
- Nuffield Department of Clinical Laboratory Sciences, University of Oxford, Oxford OX3 9DU, United Kingdom
| | - Samantha J L Knight
- Oxford NIHR Biomedical Research Centre, Oxford OX4 2PG, United Kingdom
- Wellcome Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, United Kingdom
| | - Kate Ridout
- Oxford NIHR Biomedical Research Centre, Oxford OX4 2PG, United Kingdom
- Nuffield Department of Clinical Laboratory Sciences, University of Oxford, Oxford OX3 9DU, United Kingdom
| | - Tuba Mizani
- Oxford Molecular Diagnostics Centre, Department of Oncology, University of Oxford, Oxford OX3 9DU, United Kingdom
- Oxford NIHR Biomedical Research Centre, Oxford OX4 2PG, United Kingdom
| | - Dimitris Vavoulis
- Oxford NIHR Biomedical Research Centre, Oxford OX4 2PG, United Kingdom
- Nuffield Department of Clinical Laboratory Sciences, University of Oxford, Oxford OX3 9DU, United Kingdom
| | - Richard Colling
- Oxford Molecular Diagnostics Centre, Department of Oncology, University of Oxford, Oxford OX3 9DU, United Kingdom
- Nuffield Department of Clinical Laboratory Sciences, University of Oxford, Oxford OX3 9DU, United Kingdom
| | - Pavlos Antoniou
- Cambridge University Hospitals NHS Foundation Trust, Cambridge Biomedical Campus, Cambridge CB2 0QQ, United Kingdom
| | - Erika M Kvikstad
- Oxford NIHR Biomedical Research Centre, Oxford OX4 2PG, United Kingdom
- Wellcome Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, United Kingdom
| | - Melissa M Pentony
- Oxford NIHR Biomedical Research Centre, Oxford OX4 2PG, United Kingdom
- Wellcome Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, United Kingdom
| | - Angela Hamblin
- Department of Haematology, Oxford University Hospitals NHS Foundation Trust, Oxford OX3 9DU, United Kingdom
| | - Andrew Protheroe
- Oxford Cancer and Haematology Centre, Oxford University Hospitals NHS Foundation Trust, Oxford OX3 7LE, United Kingdom
| | - Marina Parton
- Breast Unit, Royal Marsden NHS Foundation Trust and Kingston NHS Foundation Trust, London SW3 6JJ, United Kingdom
| | - Ketan A Shah
- Department of Cellular Pathology, Oxford University Hospitals NHS Foundation Trust, Oxford OX3 9DU, United Kingdom
| | - Zsolt Orosz
- Breast Unit, Royal Marsden NHS Foundation Trust and Kingston NHS Foundation Trust, London SW3 6JJ, United Kingdom
- Department of Cellular Pathology, Oxford University Hospitals NHS Foundation Trust, Oxford OX3 9DU, United Kingdom
| | - Nick Athanasou
- Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford OX3 7LD, United Kingdom
| | - Bass Hassan
- Sir William Dunn School of Pathology, University of Oxford, Oxford OX1 3RE, United Kingdom
| | - Adrienne M Flanagan
- University College London, Cancer Institute and Royal National Orthopaedic NHS Hospital, London WC1E 6BT, United Kingdom
| | - Ahmed Ahmed
- Nuffield Department of Obstetrics and Gynaecology, University of Oxford, Oxford OX3 9DU, United Kingdom
| | - Stuart Winter
- Department of Ear Nose and Throat-Head and Neck Surgery, Oxford University Hospitals, Oxford OX3 9DU, United Kingdom
| | - Adrian Harris
- Department of Oncology, University of Oxford, Oxford OX3 7DQ, United Kingdom
| | - Ian Tomlinson
- Wellcome Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, United Kingdom
| | - Niko Popitsch
- The Children's Cancer Research Institute (CCRI), 1090 Vienna, Austria
| | - David Church
- Wellcome Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, United Kingdom
| | - Jenny C Taylor
- Oxford NIHR Biomedical Research Centre, Oxford OX4 2PG, United Kingdom
- Wellcome Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, United Kingdom
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Epstein-Barr Virus Induces Adhesion Receptor CD226 (DNAM-1) Expression during Primary B-Cell Transformation into Lymphoblastoid Cell Lines. mSphere 2017; 2:mSphere00305-17. [PMID: 29202043 PMCID: PMC5705804 DOI: 10.1128/msphere.00305-17] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 07/07/2017] [Accepted: 10/16/2017] [Indexed: 12/14/2022] Open
Abstract
Epstein-Barr virus (EBV), an oncogenic herpesvirus, infects and transforms primary B cells into immortal lymphoblastoid cell lines (LCLs), providing a model for EBV-mediated tumorigenesis. EBV transformation stimulates robust homotypic aggregation, indicating that EBV induces molecules that mediate cell-cell adhesion. We report that EBV potently induced expression of the adhesion molecule CD226, which is not normally expressed on B cells. We found that early after infection of primary B cells, EBV promoted an increase in CD226 mRNA and protein expression. CD226 levels increased further from early proliferating EBV-positive B cells to LCLs. We found that CD226 expression on B cells was independent of B-cell activation as CpG DNA failed to induce CD226 to the extent of EBV infection. CD226 expression was high in EBV-infected B cells expressing the latency III growth program, but low in EBV-negative and EBV latency I-infected B-lymphoma cell lines. We validated this correlation by demonstrating that the latency III characteristic EBV NF-κB activator, latent membrane protein 1 (LMP1), was sufficient for CD226 upregulation and that CD226 was more highly expressed in lymphomas with increased NF-κB activity. Finally, we found that CD226 was not important for LCL steady-state growth, survival in response to apoptotic stress, homotypic aggregation, or adhesion to activated endothelial cells. These findings collectively suggest that EBV induces expression of a cell adhesion molecule on primary B cells that may play a role in the tumor microenvironment of EBV-associated B-cell malignancies or facilitate adhesion in the establishment of latency in vivo. IMPORTANCE Epstein-Barr virus (EBV) is a common human herpesvirus that establishes latency in B cells. While EBV infection is asymptomatic for most individuals, immune-suppressed individuals are at significantly higher risk of a form of EBV latent infection in which infected B cells are reactivated, grow unchecked, and generate lymphomas. This form of latency is modeled in the laboratory by infecting B cells from the blood of normal human donors in vitro. In this model, we identified a protein called CD226 that is induced by EBV but is not normally expressed on B cells. Rather, it is known to play a role in aggregation and survival signaling of non-B cells in the immune system. Cultures of EBV-infected cells adhere to one another in "clumps," and while the proteins that are responsible for this cellular aggregation are not fully understood, we hypothesized that this form of cellular aggregation may provide a survival advantage. In this article, we characterize the mechanism by which EBV induces this protein and its expression on lymphoma tissue and cell lines and characterize EBV-infected cell lines in which CD226 has been knocked out.
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Mercorio R, Bonzini M, Angelici L, Iodice S, Delbue S, Mariani J, Apostoli P, Pesatori AC, Bollati V. Effects of metal-rich particulate matter exposure on exogenous and endogenous viral sequence methylation in healthy steel-workers. ENVIRONMENTAL RESEARCH 2017; 159:452-457. [PMID: 28858759 DOI: 10.1016/j.envres.2017.08.042] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Academic Contribution Register] [Received: 06/07/2017] [Revised: 08/23/2017] [Accepted: 08/23/2017] [Indexed: 06/07/2023]
Abstract
BACKGROUND Inhaled particles have been shown to produce systemic changes in DNA methylation. Global hypomethylation has been associated to viral sequence reactivation, possibly linked to the activation of pro-inflammatory pathways occurring after exposure. This observation provides a rationale to investigate viral sequence (both exogenous and endogenous) methylation in association to metal-rich particulate matter exposure. To verify this hypothesis, we chose the Wp promoter of the Epstein-Barr Virus (EBV-Wp) and the promoter of the human-endogenous-retrovirus w (HERV-w), respectively as a paradigm of an exogenous and an endogenous retroviral sequence, to be investigated by bisulfite PCR Pyrosequencing. We enrolled 63 male workers in an electric furnace steel plant, exposed to high level of metal-rich particulate matter. RESULTS Comparing samples obtained in the first day of a work week (time 0-baseline, after 2 days off work) and the samples obtained after 3 days of work (time 1-post exposure), the mean methylation of EBV-Wp was significantly higher at baseline compared to post-exposure (meanbaseline = 56.7%5mC; meanpost-exposure = 47.9%5mC; p-value = 0.009), whereas the mean methylation of HERV-w did not significantly differ. Individual exposure to inhalable particles and metals was estimated based on measures in all working areas and time spent by the study subjects in each area. In a regression model adjusted for age, body mass index and smoking, PM and metal components had a positive association with EBV-Wp methylation (i.e. PM10: β = 5.99, p-value < 0.038; nickel: β = 17.82, p-value = 0.02; arsenic: β = 13.59, p-value < 0.015). CONCLUSIONS The difference observed comparing baseline and post-exposure samples may be suggestive of a rapid change in EBV methylation induced by air particles, while correlation between EBV methylation and PM/metal exposure may represent a more stable adaptive mechanism. Future studies investigating a larger panel of viral sequences could better elucidate possible mechanisms and their role in pro-inflammatory pathways leading to systemic health effects.
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Affiliation(s)
- Roberta Mercorio
- EPIGET LAB, Department of Clinical Sciences and Community Health, Università degli Studi di Milano, Via san Barnaba 8, 20122 Milan, Italy
| | - Matteo Bonzini
- EPIGET LAB, Department of Clinical Sciences and Community Health, Università degli Studi di Milano, Via san Barnaba 8, 20122 Milan, Italy; Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Laura Angelici
- EPIGET LAB, Department of Clinical Sciences and Community Health, Università degli Studi di Milano, Via san Barnaba 8, 20122 Milan, Italy
| | - Simona Iodice
- Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Serena Delbue
- Department of Biomedical, Surgical and Dental Sciences, University of Milano, Via Pascal, 36-20133 Milan, Italy
| | - Jacopo Mariani
- EPIGET LAB, Department of Clinical Sciences and Community Health, Università degli Studi di Milano, Via san Barnaba 8, 20122 Milan, Italy
| | - Pietro Apostoli
- Occupational Medicine and Industrial Hygiene, University of Brescia, Department of Experimental and Applied Medicine, Brescia, Italy
| | - Angela Cecilia Pesatori
- EPIGET LAB, Department of Clinical Sciences and Community Health, Università degli Studi di Milano, Via san Barnaba 8, 20122 Milan, Italy; Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Valentina Bollati
- EPIGET LAB, Department of Clinical Sciences and Community Health, Università degli Studi di Milano, Via san Barnaba 8, 20122 Milan, Italy.
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Tak Manesh A, Azizi G, Heydari A, Kiaee F, Shaghaghi M, Hossein-Khannazer N, Yazdani R, Abolhassani H, Aghamohammadi A. Epidemiology and pathophysiology of malignancy in common variable immunodeficiency? Allergol Immunopathol (Madr) 2017; 45:602-615. [PMID: 28411962 DOI: 10.1016/j.aller.2017.01.006] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 10/11/2016] [Revised: 12/18/2016] [Accepted: 01/07/2017] [Indexed: 02/06/2023]
Abstract
Common variable immunodeficiency (CVID) is a diagnostic category of primary immunodeficiency (PID) which may present with heterogeneous disorders including recurrent infections, autoimmunity, granulomatous diseases, lymphoid and other types of malignancies. Generally, the incidence of malignancy in CVID patients is around 1.5-20.7% and usually occurs during the 4th-6th decade of life. Non-Hodgkin lymphoma is the most frequent malignancy, followed by epithelial tumours of stomach, breast, bladder and cervix. The exact pathological mechanisms for cancer development in CVID are not fully determined; however, several mechanisms including impaired genetic stability, genetic predisposition, immune dysregulation, impaired clearance of oncogenic viruses and bacterial infections, and iatrogenic causes have been proposed to contribute to the high susceptibility of these patients to malignancies.
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Affiliation(s)
| | - G Azizi
- Department of Laboratory Medicine, Imam Hassan Mojtaba Hospital, Alborz University of Medical Sciences, Karaj, Iran; Research Center for Immunodeficiencies, Pediatrics Center of Excellence, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran
| | - A Heydari
- Research Center for Immunodeficiencies, Pediatrics Center of Excellence, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran
| | - F Kiaee
- Research Center for Immunodeficiencies, Pediatrics Center of Excellence, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran
| | - M Shaghaghi
- Research Center for Immunodeficiencies, Pediatrics Center of Excellence, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran
| | - N Hossein-Khannazer
- Department of Immunology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - R Yazdani
- Department of Immunology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - H Abolhassani
- Research Center for Immunodeficiencies, Pediatrics Center of Excellence, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran; Division of Clinical Immunology, Department of Laboratory Medicine, Karolinska Institute at Karolinska University Hospital Huddinge, Stockholm, Sweden
| | - A Aghamohammadi
- Research Center for Immunodeficiencies, Pediatrics Center of Excellence, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran.
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Suares A, Mori Sequeiros Garcia M, Paz C, González-Pardo V. Antiproliferative effects of Bortezomib in endothelial cells transformed by viral G protein-coupled receptor associated to Kaposi's sarcoma. Cell Signal 2017; 32:124-132. [DOI: 10.1016/j.cellsig.2017.01.025] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 11/01/2016] [Revised: 01/30/2017] [Accepted: 01/30/2017] [Indexed: 10/20/2022]
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Gholizadeh P, Eslami H, Kafil HS. Carcinogenesis mechanisms of Fusobacterium nucleatum. Biomed Pharmacother 2017; 89:918-925. [PMID: 28292019 DOI: 10.1016/j.biopha.2017.02.102] [Citation(s) in RCA: 109] [Impact Index Per Article: 13.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 01/31/2017] [Revised: 02/23/2017] [Accepted: 02/27/2017] [Indexed: 02/06/2023] Open
Abstract
Transformed cells of cancers may be related to stromal cells, immune cells, and some bacteria such as Fusobacterium nucleatum. This review aimed to evaluate carcinogenesis mechanisms of Fusobacterium spp. in the oral cavity, pancreatic and colorectal cancers. These cancers are the three of the ten most prevalence cancer in the worldwide. Recent findings demonstrated that F. nucleatum could be considered as the risk factor for these cancers. The most important carcinogenesis mechanisms of F. nucleatum are chronic infection, interaction of cell surface molecules of these bacteria with immune system and stromal cells, immune evasion and immune suppression. However, there are some uncertainty carcinogenesis mechanisms about these bacteria, but this review evaluates almost all the known mechanisms. Well-characterized virulence factors of F. nucleatum such as FadA, Fap2, LPS and cell wall extracts may act as effector molecules in the shift of normal epithelial cells to tumor cells. These molecules may provide new targets, drugs, and strategies for therapeutic intervention.
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Affiliation(s)
- Pourya Gholizadeh
- Hematology and Oncology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Hosein Eslami
- Dental and Periodontal Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Hossein Samadi Kafil
- Infectious and Tropical Medicine Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
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47
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Guan H, Miao H, Ma N, Lu W, Luo B. Correlations between Epstein-Barr virus and acute leukemia. J Med Virol 2017; 89:1453-1460. [DOI: 10.1002/jmv.24797] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 10/16/2016] [Accepted: 02/09/2017] [Indexed: 11/07/2022]
Affiliation(s)
- Hongzai Guan
- Department of Hematology; Qingdao University Medical College; Qingdao China
| | - Hongxia Miao
- Department of Hematology; Qingdao University Medical College; Qingdao China
| | - Na Ma
- Department of Hematology; Ji Ning Medical College; Ji Ning China
| | - Wei Lu
- Department of Hematology; Qingdao University Medical College; Qingdao China
| | - Bing Luo
- Departmentof Microbiology; Qingdao University Medical College; Qingdao China
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48
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Dharnidharka VR. Peripheral Blood Epstein-Barr Viral Nucleic Acid Surveillance as a Marker for Posttransplant Cancer Risk. Am J Transplant 2017; 17:611-616. [PMID: 27458691 DOI: 10.1111/ajt.13982] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 02/29/2016] [Revised: 07/17/2016] [Accepted: 07/18/2016] [Indexed: 01/25/2023]
Abstract
Several viruses, such as Epstein-Barr virus, are now known to be associated with several human cancers, but not all patients with these viral infections develop cancer. In transplantation, such viruses often have a prolonged time gap from infection to cancer development, and many are preceded by a period of circulating and detectable nucleic acids in the peripheral blood compartment. The interpretation of a viral load as a measure of posttransplant risk of developing cancer depends on the virus, the cancer and associated pathogenic factors. This review describes the current state of knowledge regarding the utility and limitations of peripheral blood nucleic acid testing for Epstein-Barr virus in surveillance and risk prediction for posttransplant lymphoproliferative disorders.
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Affiliation(s)
- V R Dharnidharka
- Division of Pediatric Nephrology, Washington University School of Medicine and St. Louis Children's Hospital, St. Louis, MO
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49
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Weiss M, Daeschlein G, Kramer A, Burchardt M, Brucker S, Wallwiener D, Stope MB. Virucide properties of cold atmospheric plasma for future clinical applications. J Med Virol 2017; 89:952-959. [DOI: 10.1002/jmv.24701] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Accepted: 09/26/2016] [Indexed: 12/30/2022]
Affiliation(s)
- M. Weiss
- Department of Gynecology and Obstetrics; University Medicine Tübingen; Tübingen Germany
- Department of Urology; University Medicine Greifswald; Greifswald Germany
| | - G. Daeschlein
- Department of Dermatology; University Medicine Greifswald; Greifswald Germany
| | - A. Kramer
- Department of Hygiene and Environmental Medicine; University Medicine Greifswald; Greifswald Germany
| | - M. Burchardt
- Department of Urology; University Medicine Greifswald; Greifswald Germany
| | - S. Brucker
- Department of Gynecology and Obstetrics; University Medicine Tübingen; Tübingen Germany
| | - D. Wallwiener
- Department of Gynecology and Obstetrics; University Medicine Tübingen; Tübingen Germany
| | - M. B. Stope
- Department of Urology; University Medicine Greifswald; Greifswald Germany
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50
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Wang X, Hu M, Xing F, Wang M, Wang B, Qian D. Human cytomegalovirus infection promotes the stemness of U251 glioma cells. J Med Virol 2017; 89:878-886. [PMID: 27714816 DOI: 10.1002/jmv.24708] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Accepted: 10/05/2016] [Indexed: 12/11/2022]
Abstract
Glioblastoma (GBM) are the most common and aggressive tumors of human brain. Recent studies showed that human cytomegalovirus (HCMV) can induce malignant transformation of tumor cells to maintain stemness. Transcription factor 5 (ATF5) is an anti-apoptotic protein that is highly expressed in malignant glioma. The aim of this study is to investigate the effect of HCMV infection on the stem cell makers of U251 cells. U251 cells were infected by AD169 HCMV strain (MOI = 1). The expression of stem cell makers (CD133, NES, Notch1) in infected U251 cells were compared with the expression in uninfected U251 cell to see the difference between them. Then, the changes of cell proliferation activity and the expression level of Notch intracellular domain (NICD), Notch1, ATF5, and IE protein were detected in the infected cells, and the expressions of Notch1 and NICD were increased. Cell proliferation assay showed that HCMV infection significantly increased the proliferation. These cells could form tumor spheres in non-adherent conditions. Consistent with these findings, the effect of silencing ATF5 on the proliferation of HCMV-infected U251 cells was also examined. The result shows that short interfering RNA-mediated ATF5 downregulation inhibited this process. These findings imply that HCMV infection may regulate ATF5 signaling pathway to increase cell malignant traits and maintain stemness. J. Med. Virol. 89:878-886, 2017. © 2016 Wiley Periodicals, Inc.
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Affiliation(s)
- Xinhui Wang
- Department of Microbiology, Qingdao University Medical College, Qingdao, Shandong, P.R. China
| | - Ming Hu
- Department of Microbiology, Qingdao University Medical College, Qingdao, Shandong, P.R. China
| | - Feifei Xing
- Department of Microbiology, Qingdao University Medical College, Qingdao, Shandong, P.R. China
| | - Mengyuan Wang
- Department of Microbiology, Qingdao University Medical College, Qingdao, Shandong, P.R. China
| | - Bin Wang
- Department of Microbiology, Qingdao University Medical College, Qingdao, Shandong, P.R. China
| | - Dongmeng Qian
- Department of Microbiology, Qingdao University Medical College, Qingdao, Shandong, P.R. China
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