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De Rose F, Carmen De Santis M, Lucidi S, Ray Colciago R, Marino L, Cucciarelli F, La Rocca E, Di Pressa F, Lohr F, Vanoni V, Meduri B. Dose constraints in breast cancer radiotherapy. A critical review. Radiother Oncol 2025; 202:110591. [PMID: 39427931 DOI: 10.1016/j.radonc.2024.110591] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2024] [Revised: 09/13/2024] [Accepted: 10/13/2024] [Indexed: 10/22/2024]
Abstract
Radiotherapy plays an essential role in the treatment of breast cancer (BC). Recent advances in treatment technology and radiobiological knowledge have a major impact in BC patients with locoregional disease as the majority are now long-term survivors. Over the last three decades, intensity-modulated radiotherapy (IMRT), volumetric-modulated arc therapy (VMAT) and deep inspiration breath-hold (DIBH) techniques, together with the increasing adoption of moderately hypofractionated and ultra-hypofractionated treatment schedules as well as the possibility to offer partial breast radiotherapy to a well-defined patient subset have significantly changed radiotherapy for BC patients. As dose-volume constraints (DVCs) have to be adapted to these new treatment paradigms we have reviewed available evidence-based data concerning dose-constraints for the main organs at risk (OARs) that apply to the treatment of whole breast/chest wall radiotherapy, whole breast/chest wall radiotherapy including regional nodal irradiation (RNI) and partial breast irradiation (PBI), for the most relevant fractionation schedules that have been introduced recently. This narrative review provides a comprehensive summary that may help to harmonize treatment planning strategies.
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Affiliation(s)
| | - Maria Carmen De Santis
- Radiation Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milan, Italy
| | | | | | - Lorenza Marino
- Servizio di Radioterapia, Humanitas Istituto Clinico Catanese, Misterbianco, CT, Italy
| | - Francesca Cucciarelli
- Radiotherapy Department, Azienda Ospedaliero Universitaria delle Marche, Ancona, Italy
| | - Eliana La Rocca
- Department of Radiation Oncology, Azienda Ospedaliera Universitaria Integrata di Verona, Verona, Italy
| | - Francesca Di Pressa
- Department of Radiation Oncology, University Hospital of Modena, Modena, Italy
| | - Frank Lohr
- Proton Therapy Unit, APSS, Trento, Italy; CISMED - Centro Interdipartimentale di Scienze Mediche, University of Trento, Trento, Italy
| | | | - Bruno Meduri
- Department of Radiation Oncology, University Hospital of Modena, Modena, Italy
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Elawa S, Fredriksson I, Steinvall I, Zötterman J, Farnebo S, Tesselaar E. Skin perfusion and oxygen saturation after mastectomy and radiation therapy in breast cancer patients. Breast 2024; 75:103704. [PMID: 38460441 PMCID: PMC10943105 DOI: 10.1016/j.breast.2024.103704] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2024] [Revised: 03/04/2024] [Accepted: 03/05/2024] [Indexed: 03/11/2024] Open
Abstract
The pathophysiological mechanism behind complications associated with postmastectomy radiotherapy (PMRT) and subsequent implant-based breast reconstruction are not completely understood. The aim of this study was to examine if there is a relationship between PMRT and microvascular perfusion and saturation in the skin after mastectomy and assess if there is impaired responsiveness to a topically applied vasodilator (Methyl nicotinate - MN). Skin microvascular perfusion and oxygenation >2 years after PMRT were measured using white light diffuse reflectance spectroscopy (DRS) and laser Doppler flowmetry (LDF) in the irradiated chest wall of 31 women with the contralateral breast as a control. In the non-irradiated breast, the perfusion after application of MN (median 0.84, 25th-75th centile 0.59-1.02 % RBC × mm/s) was higher compared to the irradiated chest wall (median 0.51, 25th-75th centile 0.21-0.68 % RBC × mm/s, p < 0.001). The same phenomenon was noted for saturation (median 91 %, 25th-75th centile 89-94 % compared to 89 % 25th-75th centile 77-93 %, p = 0.001). Eight of the women (26%) had a ≥10 % difference in skin oxygenation between the non-irradiated breast and the irradiated chest wall. These results indicate that late microvascular changes caused by radiotherapy of the chest wall significantly affect skin perfusion and oxygenation.
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Affiliation(s)
- Sherif Elawa
- Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden; Department of Plastic Surgery, Hand Surgery, and Burns, Linköping University, Linköping, Sweden.
| | - Ingemar Fredriksson
- Department of Biomedical Engineering, Linköping University, Linköping, Sweden; Perimed AB, Järfälla, Stockholm, Sweden
| | - Ingrid Steinvall
- Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden; Department of Plastic Surgery, Hand Surgery, and Burns, Linköping University, Linköping, Sweden
| | - Johan Zötterman
- Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden; Department of Plastic Surgery, Hand Surgery, and Burns, Linköping University, Linköping, Sweden
| | - Simon Farnebo
- Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden; Department of Plastic Surgery, Hand Surgery, and Burns, Linköping University, Linköping, Sweden
| | - Erik Tesselaar
- Department of Medical Radiation Physics, Department of Health, Medicine and Caring Sciences, Linköping University, Linköping, Sweden
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Sterling J, Rahman SN, Varghese A, Angulo JC, Nikolavsky D. Complications after Prostate Cancer Treatment: Pathophysiology and Repair of Post-Radiation Urethral Stricture Disease. J Clin Med 2023; 12:3950. [PMID: 37373644 DOI: 10.3390/jcm12123950] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2023] [Revised: 06/03/2023] [Accepted: 06/06/2023] [Indexed: 06/29/2023] Open
Abstract
Radiation therapy (RT) in the management of pelvic cancers remains a clinical challenge to urologists given the sequelae of urethral stricture disease secondary to fibrosis and vascular insults. The objective of this review is to understand the physiology of radiation-induced stricture disease and to educate urologists in clinical practice regarding future prospective options clinicians have to deal with this condition. The management of post-radiation urethral stricture consists of conservative, endoscopic, and primary reconstructive options. Endoscopic approaches remain an option, but with limited long-term success. Despite concerns with graft take, reconstructive options such as urethroplasties in this population with buccal grafts have shown long-term success rates ranging from 70 to 100%. Robotic reconstruction is augmenting previous options with faster recovery times. Radiation-induced stricture disease is challenging with multiple interventions available, but with successful outcomes demonstrated in various cohorts including urethroplasties with buccal grafts and robotic reconstruction.
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Affiliation(s)
- Joshua Sterling
- Yale School of Medicine, 20 York Street, New Haven, CT 06511, USA
| | - Syed N Rahman
- Yale School of Medicine, 20 York Street, New Haven, CT 06511, USA
| | - Ajin Varghese
- New York College of Osteopathic Medicine, 8000 Old Westbury, Glen Head, NY 11545, USA
| | - Javier C Angulo
- Faculty of Biomedical Sciences, Universidad Europea, 28905 Madrid, Spain
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Tevlin R, Longaker MT, Wan DC. Deferoxamine to Minimize Fibrosis During Radiation Therapy. Adv Wound Care (New Rochelle) 2022; 11:548-559. [PMID: 34074152 PMCID: PMC9347384 DOI: 10.1089/wound.2021.0021] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2021] [Accepted: 05/14/2021] [Indexed: 01/29/2023] Open
Abstract
Significance: By 2030, there will be >4 million radiation-treated cancer survivors living in the United States. Irradiation triggers inflammation, fibroblast activation, and extracellular matrix deposition in addition to reactive oxygen species generation, leading to a chronic inflammatory response. Radiation-induced fibrosis (RIF) is a progressive pathology resulting in skin pigmentation, reduced elasticity, ulceration and dermal thickening, cosmetic deformity, pain, and the need for reconstructive surgery. Recent Advances: Deferoxamine (DFO) is a U.S. Food and Drug Administration (FDA)-approved iron chelator for blood dyscrasia management, which has been found to be proangiogenic, to decrease free radical formation, and reduce cell death. DFO has shown great promise in the treatment and prophylaxis of RIF in preclinical studies. Critical Issues: Systemic DFO has a short half-life and is cumbersome to deliver to patients intravenously. Transdermal DFO delivery is complicated by its high atomic mass and hydrophilicity, preventing stratum corneum penetration. A transdermal drug delivery system was developed to address these challenges, in addition to a strategy for topical administration. Future Directions: DFO has great potential to translate from bench to bedside. An important step in translation of DFO for RIF prophylaxis is to ensure that DFO treatment does not affect the efficacy of radiation therapy. Furthermore, after an initial plethora of studies reporting DFO treatment by intravenous and subcutaneous routes, a significant advantage of recent studies is the success of transdermal and topical delivery. Given the strong foundation of basic scientific research supporting the use of DFO treatment on RIF, clinicians will be closely following the results of the ongoing human studies.
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Affiliation(s)
- Ruth Tevlin
- Division of Plastic and Reconstructive Surgery, and Stanford University School of Medicine, Stanford, California, USA
- Hagey Laboratory for Pediatric Regenerative Medicine, Department of Surgery, Stanford University School of Medicine, Stanford, California, USA
- School of Postgraduate Studies, Royal College of Surgeons in Ireland, Dublin, Ireland
| | - Michael T. Longaker
- Division of Plastic and Reconstructive Surgery, and Stanford University School of Medicine, Stanford, California, USA
- Hagey Laboratory for Pediatric Regenerative Medicine, Department of Surgery, Stanford University School of Medicine, Stanford, California, USA
- Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, California, USA
| | - Derrick C. Wan
- Division of Plastic and Reconstructive Surgery, and Stanford University School of Medicine, Stanford, California, USA
- Hagey Laboratory for Pediatric Regenerative Medicine, Department of Surgery, Stanford University School of Medicine, Stanford, California, USA
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P144 a Transforming Growth Factor Beta Inhibitor Peptide, Generates Antifibrogenic Effects in a Radiotherapy Induced Fibrosis Model. Curr Oncol 2022; 29:2650-2661. [PMID: 35448191 PMCID: PMC9024500 DOI: 10.3390/curroncol29040217] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2022] [Revised: 04/06/2022] [Accepted: 04/08/2022] [Indexed: 12/04/2022] Open
Abstract
Radiation-induced fibrosis (RIF) is a severe side effect related with soft tissues sarcomas (STS) radiotherapy. RIF is a multicellular process initiated primarily by TGF-β1 that is increased in irradiated tissue, whose signaling leads to intracellular Smad2/3 phosphorylation and further induction of profibrotic target genes. P144 (Disetertide©) is a peptide inhibitor of TGF-β1 and is proposed as a candidate compound for reducing RIF associated wound healing problems and muscle fibrosis in STS. Methods: A treatment and control group of WNZ rabbits were employed to implement a brachytherapy animal model, through catheter implantation at the lower limb. Two days after implantation, animals received 20 Gy isodosis, intended to induce a high RIF grade. The treatment group received intravenous P144 administration following a brachytherapy session, repeated at 24–72 h post-radiation, while the control group received placebo. Four weeks later, affected muscular tissues underwent histological processing for collagen quantification and P-Smad2/3 immunohistochemistry through image analysis. Results: High isodosis Brachytherapy produced remarkable fibrosis in this experimental model. Results showed retained macro and microscopical morphology of muscle in the P144 treated group, with reduced extracellular matrix fibrosis, with a lower area of collagen deposition measured through Masson’s trichrome staining. Intravenous P144 also induced a significant reduction in Smad2/3 phosphorylation levels compared with the placebo group. Conclusions: P144 administration clearly reduces RIF and opens a new potential co-treatment approach to reduce complications in soft tissue sarcoma (STS) radiotherapy. Further studies are required to establish whether the dosage and timing optimization of P144 administration, in different RIF phases, might entirely avoid fibrosis associated with STS brachytherapy.
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Inflammation, Fibrosis and Cancer: Mechanisms, Therapeutic Options and Challenges. Cancers (Basel) 2022; 14:cancers14030552. [PMID: 35158821 PMCID: PMC8833582 DOI: 10.3390/cancers14030552] [Citation(s) in RCA: 41] [Impact Index Per Article: 13.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2021] [Revised: 01/15/2022] [Accepted: 01/17/2022] [Indexed: 01/09/2023] Open
Abstract
Uncontrolled inflammation is a salient factor in multiple chronic inflammatory diseases and cancers. In this review, we provided an in-depth analysis of the relationships and distinctions between uncontrolled inflammation, fibrosis and cancers, while emphasizing the challenges and opportunities of developing novel therapies for the treatment and/or management of these diseases. We described how drug delivery systems, combination therapy and the integration of tissue-targeted and/or pathways selective strategies could overcome the challenges of current agents for managing and/or treating chronic inflammatory diseases and cancers. We also recognized the value of the re-evaluation of the disease-specific roles of multiple pathways implicated in the pathophysiology of chronic inflammatory diseases and cancers-as well as the application of data from single-cell RNA sequencing in the success of future drug discovery endeavors.
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Jafari F, Safaei AM, Hosseini L, Asadian S, Kamangar TM, Zadehbagheri F, Rezaeian N. The role of cardiac magnetic resonance imaging in the detection and monitoring of cardiotoxicity in patients with breast cancer after treatment: a comprehensive review. Heart Fail Rev 2021; 26:679-697. [PMID: 33029698 DOI: 10.1007/s10741-020-10028-y] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 09/15/2020] [Indexed: 01/04/2023]
Abstract
The use of chemotherapy medicines for breast cancer (BC) has been associated with an increased risk of cardiotoxicity. In recent years, there have been growing interests regarding the application of cardiovascular magnetic resonance (CMR) imaging, a safe and noninvasive modality, with the potential to identify subtle morphological and functional changes in the myocardium. In this investigation, we aimed to review the performance of various CMR methods in diagnosing cardiotoxicity in BC, induced by chemotherapy or radiotherapy. For this purpose, we reviewed the literature available in PubMed, MEDLINE, Cochrane, Google Scholar, and Scopus databases. Our literature review showed that CMR is a valuable modality for identifying and predicting subclinical cardiotoxicity induced by chemotherapy. The novel T1, T2, and extracellular volume mapping techniques may provide critical information about cardiotoxicity, in addition to other CMR features such as functional and structural changes. However, further research is needed to verify the exact role of these methods in identifying cardiotoxicity and patient management. Since multiple studies have reported the improvement of left ventricular performance following the termination of chemotherapy regimens, CMR remains an essential imaging tool for the prediction of cardiotoxicity and, consequently, decreases the mortality rate of BC due to heart failure.
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Affiliation(s)
- Fatemeh Jafari
- Department of Radiation Oncology, Cancer Institute, Tehran University of Medical Sciences, Tehran, Iran
- Radiation Oncology Research Center (RORC), Cancer Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Afsane Maddah Safaei
- Radiation Oncology Research Center (RORC), Cancer Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Leila Hosseini
- North Khorasan University of Medical Sciences, Bojnurd, Iran
| | - Sanaz Asadian
- Rajaie Cardiovascular Medical and Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Tara Molanaie Kamangar
- Radiation Oncology Research Center (RORC), Cancer Institute, Tehran University of Medical Sciences, Tehran, Iran
| | | | - Nahid Rezaeian
- Rajaie Cardiovascular Medical and Research Center, Iran University of Medical Sciences, Tehran, Iran.
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PM014 attenuates radiation-induced pulmonary fibrosis via regulating NF-kB and TGF-b1/NOX4 pathways. Sci Rep 2020; 10:16112. [PMID: 32999298 PMCID: PMC7527517 DOI: 10.1038/s41598-020-72629-9] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2020] [Accepted: 09/04/2020] [Indexed: 12/31/2022] Open
Abstract
Radiation therapy is the mainstay in the treatment of lung cancer, and lung fibrosis is a radiotherapy-related major side effect that can seriously reduce patient’s quality of life. Nevertheless, effective strategies for protecting against radiation therapy-induced fibrosis have not been developed. Hence, we investigated the radioprotective effects and the underlying mechanism of the standardized herbal extract PM014 on radiation-induced lung fibrosis. Ablative radiation dose of 75 Gy was focally delivered to the left lung of mice. We evaluated the effects of PM014 on radiation-induced lung fibrosis in vivo and in an in vitro model. Lung volume and functional changes were evaluated using the micro-CT and flexiVent system. Fibrosis-related molecules were evaluated by immunohistochemistry, western blot, and real-time PCR. A orthotopic lung tumour mouse model was established using LLC1 cells. Irradiated mice treated with PM014 showed a significant improvement in collagen deposition, normal lung volume, and functional lung parameters, and these therapeutic effects were better than those of amifostine. PM104 attenuated radiation-induced increases in NF-κB activity and inhibited radiation-induced p65 translocation, ROS production, DNA damage, and epithelial-mesenchymal transition. PM104 effectively alleviated fibrosis in an irradiated orthotopic mouse lung tumour model while not attenuating the efficacy of the radiation therapy by reduction of the tumour. Standardized herbal extract PM014 may be a potential therapeutic agent that is able to increase the efficacy of radiotherapy by alleviating radiation-induced lung fibrosis.
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Wu SY, Chen YT, Tsai GY, Hsu FY, Hwang PA. Protective Effect of Low-Molecular-Weight Fucoidan on Radiation-Induced Fibrosis Through TGF-β1/Smad Pathway-Mediated Inhibition of Collagen I Accumulation. Mar Drugs 2020; 18:E136. [PMID: 32120789 PMCID: PMC7142431 DOI: 10.3390/md18030136] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2020] [Revised: 02/20/2020] [Accepted: 02/25/2020] [Indexed: 12/22/2022] Open
Abstract
Radiation-induced fibrosis (RIF) occurs after radiation therapy in normal tissues due to excessive production and deposition of extracellular matrix proteins and collagen, possibly resulting in organ function impairment. This study investigates the effects of low-molecular-weight fucoidan (LMF) on irradiated NIH3T3 cells. Specifically, we quantified cellular metabolic activity, fibrosis-related mRNA expression, transforming growth factor beta-1 (TGF-β1), and collagen-1 protein expression, and fibroblast contractility in response to LMF. LMF pre + post-treatment could more effectively increase cellular metabolic activity compared with LMF post-treatment. LMF pre + post-treatment inhibited TGF-β1 expression, which mediates negative activation of phosphorylated Smad3 (pSmad3) and Smad4 complex formation and suppresses downstream collagen I accumulation. In addition, LMF pre + post-treatment significantly reduced actin-stress fibers in irradiated NIH3T3 cells. LMF, a natural substance obtained from brown seaweed, may be a candidate agent for preventing or inhibiting RIF.
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Affiliation(s)
- Szu-Yuan Wu
- Department of Food Nutrition and Health Biotechnology, College of Medical and Health Science, Asia University, Taichung 413, Taiwan;
- Division of Radiation Oncology, Lo-Hsu Medical Foundation, Lotung Poh-Ai Hospital, Yilan 265, Taiwan
- Department of Radiation Oncology, Wan Fang Hospital, Taipei Medical University, Taipei 116, Taiwan
- Big Data Center, Lo-Hsu Medical Foundation, Lotung Poh-Ai Hospital, Yilan 265, Taiwan
- Department of Healthcare Administration, College of Medical and Health Science, Asia University, Taichung 413, Taiwan
| | - Yu-Ting Chen
- Department of Bioscience and Biotechnology, National Taiwan Ocean University, Keelung 202, Taiwan; (Y.-T.C.); (G.-Y.T.); (F.-Y.H.)
| | - Guo-Yu Tsai
- Department of Bioscience and Biotechnology, National Taiwan Ocean University, Keelung 202, Taiwan; (Y.-T.C.); (G.-Y.T.); (F.-Y.H.)
| | - Fu-Yin Hsu
- Department of Bioscience and Biotechnology, National Taiwan Ocean University, Keelung 202, Taiwan; (Y.-T.C.); (G.-Y.T.); (F.-Y.H.)
| | - Pai-An Hwang
- Department of Bioscience and Biotechnology, National Taiwan Ocean University, Keelung 202, Taiwan; (Y.-T.C.); (G.-Y.T.); (F.-Y.H.)
- Center of Excellence for the Oceans, National Taiwan Ocean University, Keelung 202, Taiwan
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Zaher E, Fahmy E, Mahmoud K, El Kerm Y, Auf M. Assessment of the onset of radiation-induced cardiac damage after radiotherapy of breast cancer patients. ALEXANDRIA JOURNAL OF MEDICINE 2019. [DOI: 10.1016/j.ajme.2017.12.001] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Affiliation(s)
- Ebtsam Zaher
- Radiation Sciences Department, Medical Research Institute, Alexandria University, Egypt
| | - Enayat Fahmy
- Radiation Sciences Department, Medical Research Institute, Alexandria University, Egypt
| | - Kamal Mahmoud
- Clinical and Experimental Internal Medicine Department, Medical Research Institute, Alexandria University, Egypt
| | - Yasser El Kerm
- Cancer Management and Research Department, Medical Research Institute, Alexandria University, Egypt
| | - Mohammad Auf
- Demonstrator in 6th of October University, Egypt
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The impact of right ventricular function on prognosis in patients with stage III non-small cell lung cancer after concurrent chemoradiotherapy. Int J Cardiovasc Imaging 2019; 35:1009-1017. [DOI: 10.1007/s10554-019-01590-0] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/06/2019] [Accepted: 03/25/2019] [Indexed: 12/20/2022]
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miR-29b Mediates the Chronic Inflammatory Response in Radiotherapy-Induced Vascular Disease. JACC Basic Transl Sci 2019; 4:72-82. [PMID: 30847421 PMCID: PMC6390501 DOI: 10.1016/j.jacbts.2018.10.006] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/15/2018] [Revised: 10/18/2018] [Accepted: 10/18/2018] [Indexed: 12/17/2022]
Abstract
Radiotherapy is a powerful treatment strategy in patients with oncological diseases. Radiation-induced vasculopathy can dose dependently increase the risk of ischemic cardiovascular diseases (e.g., myocardial infarction, heart failure, stroke). The microRNA miR-29b is repressed in radiation-induced vasculopathy (human irradiated vs. nonirradiated tissue specimen, as well as in murine and cell culture models of irradiation). Pentraxin-3 and dipeptidyl-peptidase 4 are the main downstream effectors of miR-29b in radiation-induced vasculopathy. miR-29b mimics were able to limit pentraxin-3 and dipeptidyl-peptidase 4 levels in the irradiated vasculature (murine model) and to constrain the burden of vascular inflammation. As a consequence of the success of present-day cancer treatment, radiotherapy-induced vascular disease is emerging. This disease is caused by chronic inflammatory activation and is likely orchestrated in part by microRNAs. In irradiated versus nonirradiated conduit arteries from patients receiving microvascular free tissue transfer reconstructions, irradiation resulted in down-regulation of miR-29b and up-regulation of miR-146b. miR-29b affected inflammation and adverse wound healing through its targets pentraxin-3 and dipeptidyl-peptidase 4. In vitro and in vivo, we showed that miR-29b overexpression therapy, through inhibition of pentraxin-3 and dipeptidyl-peptidase 4, could dampen the vascular inflammatory response.
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Key Words
- Apoe–/–, apolipoprotein E knockout
- DIG, digoxigenin
- DPP4, Dpp4, dipeptidyl-peptidase 4
- FFT, free flap tissue transfer
- HCtAEC, human carotid artery endothelial cell
- HCtASMC, human carotid artery smooth muscle cell
- NR, nonirradiated
- PTX3, Ptx3, pentraxin-3
- RNA, ribonucleic acid
- SMC, smooth muscle cell
- TGF, tumor growth factor
- arteriosclerosis
- inflammation
- mRNA, messenger ribonucleic acid
- miRNA, microRNA
- microRNA
- radiotherapy
- vRTx, radiation vasculopathy
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Visweshwar N, Jaglal M, Sokol L, Djulbegovic B. Hematological Malignancies and Arterial Thromboembolism. Indian J Hematol Blood Transfus 2019; 35:611-624. [PMID: 31741612 PMCID: PMC6825093 DOI: 10.1007/s12288-019-01085-x] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2018] [Accepted: 01/21/2019] [Indexed: 01/10/2023] Open
Abstract
Established guidelines exist for prevention and treatment of venous thromboembolism in hematological malignancies, but none for arterial thromboembolism. However, arterial and venous thromboembolism share the same provoking features—including altered procoagulant factors and defective fibrinolytic system. The morbidity for arterial thromboembolism is increasing in hematological malignancies, with the advent of immunomodulatory and targeted therapy. However, survival rate for hematological malignancy is improving. Consequently, as patients with hematological malignancies live longer, comorbidities including diabetes, hypertension and dyslipidemia, may accentuate arterial thrombosis. Thus far, the scientific literature on prophylaxis and treatment for arterial thromboembolism in hematological malignancies is limited. This review highlights the pathogenesis, incidence and clinical features of arterial thromboembolism in hematological malignancies.
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Affiliation(s)
- Nathan Visweshwar
- 1Division of Hematology, University of South Florida, Tampa, FL 33612 USA
| | - Michael Jaglal
- 2Division of Medical Oncology, Moffitt Cancer Center, Tampa, FL 35316 USA
| | - Lubomir Sokol
- 2Division of Medical Oncology, Moffitt Cancer Center, Tampa, FL 35316 USA
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Quan HY, Yuan T, Hao JF. A microRNA‑125a variant, which affects its mature processing, increases the risk of radiation‑induced pneumonitis in patients with non‑small‑cell lung cancer. Mol Med Rep 2018; 18:4079-4086. [PMID: 30132551 DOI: 10.3892/mmr.2018.9406] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2015] [Accepted: 08/25/2016] [Indexed: 11/06/2022] Open
Abstract
The present study aimed to investigate the role of microRNA (miR)‑125a in the development of pneumonitis inpatients with non‑small‑cell lung cancer that received radiotherapy. In addition, the study aimed to determine how the miR‑125a affects its target, transforming growth factor β (TGFβ). Bioinformatics tools were used to identify a potential miR‑125a binding site in the 3'untranslated region of TGFβ, which was subsequently confirmed using a dual‑luciferase reporter system. In addition, tissue samples were collected from patients with lung cancer and genotyped as CC (n=36), CT (n=28) or TT (n=6). The expression levels of miR‑125a and TGFβ in these samples were determined, and CC genotype samples demonstrated upregulated miR‑125a expression, and downregulated TGFβ protein and mRNA expression compared with samples carrying the minor allele, T. To further investigate the association between the rs12976445 polymorphism and the risk of pneumonitis in patients with lung cancer that received radiotherapy, 534 lung cancer patients diagnosed with pneumonitis and 489lung cancer patients without pneumonitis were recruited. rs12976445 was shown to be significantly associated with the risk of pneumonitis. In conclusion, the rs12976445 polymorphism increased expression levels of TGFβ by decreasing the expression of miR‑125a, and therefore may be associated with the development of pneumonitis in patients with lung cancer that receive radiotherapy.
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Affiliation(s)
- Hong-Yan Quan
- Oncology Department, Shaanxi Friendship Hospital, Xi'an, Shaanxi 710008, P.R. China
| | - Tian Yuan
- Oncology Department, Shaanxi Friendship Hospital, Xi'an, Shaanxi 710008, P.R. China
| | - Jian-Feng Hao
- Biological Center, Shaanxi Friendship Hospital, Xi'an, Shaanxi 710008, P.R. China
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Abstract
Treatment sequelae such as trismus, shoulder dysfunction syndrome resulting from spinal accessory nerve palsy, and radiotherapy-induced neck fibrosis are often overlooked when in the management of head and neck cancer patients. This chapter examines these underappreciated issues and their corresponding physical therapy intervention based on current evidence. Head and neck cancer survivors must contend with these disabilities for years after treatment has been concluded. A few quit their jobs which puts a tremendous burden on them and their families with a diminished quality of life. The physical rehabilitative needs of head and neck cancer patients and useful interventions to help meet them are addressed.
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Vallée A, Lecarpentier Y, Guillevin R, Vallée JN. Interactions between TGF-β1, canonical WNT/β-catenin pathway and PPAR γ in radiation-induced fibrosis. Oncotarget 2017; 8:90579-90604. [PMID: 29163854 PMCID: PMC5685775 DOI: 10.18632/oncotarget.21234] [Citation(s) in RCA: 150] [Impact Index Per Article: 18.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2017] [Accepted: 08/17/2017] [Indexed: 12/16/2022] Open
Abstract
Radiation therapy induces DNA damage and inflammation leading to fibrosis. Fibrosis can occur 4 to 12 months after radiation therapy. This process worsens with time and years. Radiation-induced fibrosis is characterized by fibroblasts proliferation, myofibroblast differentiation, and synthesis of collagen, proteoglycans and extracellular matrix. Myofibroblasts are non-muscle cells that can contract and relax. Myofibroblasts evolve towards irreversible retraction during fibrosis process. In this review, we discussed the interplays between transforming growth factor-β1 (TGF-β1), canonical WNT/β-catenin pathway and peroxisome proliferator-activated receptor gamma (PPAR γ) in regulating the molecular mechanisms underlying the radiation-induced fibrosis, and the potential role of PPAR γ agonists. Overexpression of TGF-β and canonical WNT/β-catenin pathway stimulate fibroblasts accumulation and myofibroblast differentiation whereas PPAR γ expression decreases due to the opposite interplay of canonical WNT/β-catenin pathway. Both TGF-β1 and canonical WNT/β-catenin pathway stimulate each other through the Smad pathway and non-Smad pathways such as phosphatidylinositol 3-kinase/serine/threonine kinase (PI3K/Akt) signaling. WNT/β-catenin pathway and PPAR γ interact in an opposite manner. PPAR γ agonists decrease β-catenin levels through activation of inhibitors of the WNT pathway such as Smad7, glycogen synthase kinase-3 (GSK-3 β) and dickkopf-related protein 1 (DKK1). PPAR γ agonists also stimulate phosphatase and tensin homolog (PTEN) expression, which decreases both TGF-β1 and PI3K/Akt pathways. PPAR γ agonists by activating Smad7 decrease Smads pathway and then TGF-β signaling leading to decrease radiation-induced fibrosis. TGF-β1 and canonical WNT/β-catenin pathway promote radiation-induced fibrosis whereas PPAR γ agonists can prevent radiation-induced fibrosis.
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Affiliation(s)
- Alexandre Vallée
- Experimental and Clinical Neurosciences Laboratory, INSERM U1084, University of Poitiers, Poitiers, France.,Laboratory of Mathematics and Applications (LMA), UMR CNRS 7348, University of Poitiers, Poitiers, France
| | - Yves Lecarpentier
- Centre de Recherche Clinique, Grand Hôpital de l'Est Francilien (GHEF), Meaux, France
| | - Rémy Guillevin
- DACTIM, UMR CNRS 7348, University of Poitiers et CHU de Poitiers, Poitiers, France
| | - Jean-Noël Vallée
- Laboratory of Mathematics and Applications (LMA), UMR CNRS 7348, University of Poitiers, Poitiers, France.,CHU Amiens Picardie, University of Picardie Jules Verne (UPJV), Amiens, France
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17
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Slezak J, Kura B, Babal P, Barancik M, Ferko M, Frimmel K, Kalocayova B, Kukreja RC, Lazou A, Mezesova L, Okruhlicova L, Ravingerova T, Singal PK, Szeiffova Bacova B, Viczenczova C, Vrbjar N, Tribulova N. Potential markers and metabolic processes involved in the mechanism of radiation-induced heart injury. Can J Physiol Pharmacol 2017; 95:1190-1203. [PMID: 28750189 DOI: 10.1139/cjpp-2017-0121] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Irradiation of normal tissues leads to acute increase in reactive oxygen/nitrogen species that serve as intra- and inter-cellular signaling to alter cell and tissue function. In the case of chest irradiation, it can affect the heart, blood vessels, and lungs, with consequent tissue remodelation and adverse side effects and symptoms. This complex process is orchestrated by a large number of interacting molecular signals, including cytokines, chemokines, and growth factors. Inflammation, endothelial cell dysfunction, thrombogenesis, organ dysfunction, and ultimate failing of the heart occur as a pathological entity - "radiation-induced heart disease" (RIHD) that is major source of morbidity and mortality. The purpose of this review is to bring insights into the basic mechanisms of RIHD that may lead to the identification of targets for intervention in the radiotherapy side effect. Studies of authors also provide knowledge about how to select targeted drugs or biological molecules to modify the progression of radiation damage in the heart. New prospective studies are needed to validate that assessed factors and changes are useful as early markers of cardiac damage.
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Affiliation(s)
- Jan Slezak
- a Institute for Heart Research, Slovak Academy of Sciences, 840 05 Bratislava, Slovakia
| | - Branislav Kura
- a Institute for Heart Research, Slovak Academy of Sciences, 840 05 Bratislava, Slovakia
| | - Pavel Babal
- b Institute of Pathology, Medical Faculty of Comenius University, Bratislava, Slovakia
| | - Miroslav Barancik
- a Institute for Heart Research, Slovak Academy of Sciences, 840 05 Bratislava, Slovakia
| | - Miroslav Ferko
- a Institute for Heart Research, Slovak Academy of Sciences, 840 05 Bratislava, Slovakia
| | - Karel Frimmel
- a Institute for Heart Research, Slovak Academy of Sciences, 840 05 Bratislava, Slovakia
| | - Barbora Kalocayova
- a Institute for Heart Research, Slovak Academy of Sciences, 840 05 Bratislava, Slovakia
| | - Rakesh C Kukreja
- c Division of Cardiology, Medical College of Virginia, Virginia Commonwealth University, Richmond, VA, USA
| | - Antigone Lazou
- d School of Biology, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Lucia Mezesova
- a Institute for Heart Research, Slovak Academy of Sciences, 840 05 Bratislava, Slovakia
| | - Ludmila Okruhlicova
- a Institute for Heart Research, Slovak Academy of Sciences, 840 05 Bratislava, Slovakia
| | - Tanya Ravingerova
- a Institute for Heart Research, Slovak Academy of Sciences, 840 05 Bratislava, Slovakia
| | - Pawan K Singal
- e University of Manitoba, St. Boniface Research Centre, Winnipeg, MB R2H 2A6, Canada
| | | | - Csilla Viczenczova
- a Institute for Heart Research, Slovak Academy of Sciences, 840 05 Bratislava, Slovakia
| | - Norbert Vrbjar
- a Institute for Heart Research, Slovak Academy of Sciences, 840 05 Bratislava, Slovakia
| | - Narcis Tribulova
- a Institute for Heart Research, Slovak Academy of Sciences, 840 05 Bratislava, Slovakia
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18
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Slezák J, Kura B, Frimmel K, Zálešák M, Ravingerová T, Viczenczová C, Okruhlicová Ľ, Tribulová N. Preventive and therapeutic application of molecular hydrogen in situations with excessive production of free radicals. Physiol Res 2017; 65 Suppl 1:S11-28. [PMID: 27643933 DOI: 10.33549/physiolres.933414] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Excessive production of oxygen free radicals has been regarded as a causative common denominator of many pathological processes in the animal kingdom. Hydroxyl and nitrosyl radicals represent the major cause of the destruction of biomolecules either by a direct reaction or by triggering a chain reaction of free radicals. Scavenging of free radicals may act preventively or therapeutically. A number of substances that preferentially react with free radicals can serve as scavengers, thus increasing the internal capacity/activity of endogenous antioxidants and protecting cells and tissues against oxidative damage. Molecular hydrogen (H(2)) reacts with strong oxidants, such as hydroxyl and nitrosyl radicals, in the cells, that enables utilization of its potential for preventive and therapeutic applications. H(2) rapidly diffuses into tissues and cells without affecting metabolic redox reactions and signaling reactive species. H(2) reduces oxidative stress also by regulating gene expression, and functions as an anti-inflammatory and anti-apoptotic agent. There is a growing body of evidence based on the results of animal experiments and clinical observations that H(2) may represent an effective antioxidant for the prevention of oxidative stress-related diseases. Application of molecular hydrogen in situations with excessive production of free radicals, in particular, hydroxyl and nitrosyl radicals is relatively simple and effective, therefore, it deserves special attention.
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Affiliation(s)
- J Slezák
- Institute for Heart Research, Slovak Academy of Sciences, Bratislava, Slovakia.
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19
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Pilot study to determine the feasibility of radiation therapy for dogs with right atrial masses and hemorrhagic pericardial effusion. J Vet Cardiol 2017; 19:132-143. [DOI: 10.1016/j.jvc.2016.12.001] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2016] [Revised: 12/07/2016] [Accepted: 12/12/2016] [Indexed: 11/18/2022]
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20
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Tadic M, Cuspidi C, Hering D, Venneri L, Grozdic-Milojevic I. Radiotherapy-induced right ventricular remodelling: The missing piece of the puzzle. Arch Cardiovasc Dis 2017; 110:116-123. [DOI: 10.1016/j.acvd.2016.10.003] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/02/2016] [Revised: 10/15/2016] [Accepted: 10/18/2016] [Indexed: 11/27/2022]
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21
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Gao Y, Yao LF, Zhao Y, Wei LM, Guo P, Yu M, Cao B, Li T, Chen H, Zou ZM. The Chinese Herbal Medicine Formula mKG Suppresses Pulmonary Fibrosis of Mice Induced by Bleomycin. Int J Mol Sci 2016; 17:238. [PMID: 26891294 PMCID: PMC4783969 DOI: 10.3390/ijms17020238] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2016] [Revised: 02/03/2016] [Accepted: 02/04/2016] [Indexed: 12/26/2022] Open
Abstract
Pulmonary fibrosis (PF) is a serious progressive lung disease and it originates from inflammation-induced parenchymal injury with excessive extracellular matrix deposition to result in the destruction of the normal lung architecture. Modified Kushen Gancao Formula (mKG), derived from traditional Chinese herbal medicine, has a prominent anti-inflammatory effect. The present study is to explore the inhibitory effects of mKG on bleomycin (BLM)-induced pulmonary fibrosis in mice. mKG significantly decreased pulmonary alveolitis, fibrosis scores, and interleukin-6 (IL-6), interleukin-17 (IL-17), transforming growth factor-β (TGF-β) and hydroxyproline (HYP) levels in lung tissue of mice compared with BLM treatment. It markedly alleviated the increase of HYP content in the lung tissues and pathologic changes of pulmonary fibrosis caused by BLM instillation. In conclusion, mKG has an anti-fibrotic effect and might be employed as a therapeutic candidate agent for attenuating pulmonary fibrosis.
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Affiliation(s)
- Ying Gao
- Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100193, China.
- Department of Pharmacy, Logistics College of Chinese People's Armed Police Force, Tianjin 300309, China.
| | - Li-Fu Yao
- Department of Pharmacy, Logistics College of Chinese People's Armed Police Force, Tianjin 300309, China.
| | - Yang Zhao
- Tianjin University of Traditional Chinese Medicine, Tianjin 300193, China.
| | - Li-Man Wei
- Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100193, China.
| | - Peng Guo
- Department of Pharmacy, Logistics College of Chinese People's Armed Police Force, Tianjin 300309, China.
| | - Meng Yu
- Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100193, China.
| | - Bo Cao
- Department of Pharmacy, Logistics College of Chinese People's Armed Police Force, Tianjin 300309, China.
| | - Tan Li
- Department of Pharmacy, Logistics College of Chinese People's Armed Police Force, Tianjin 300309, China.
| | - Hong Chen
- Department of Pharmacy, Logistics College of Chinese People's Armed Police Force, Tianjin 300309, China.
| | - Zhong-Mei Zou
- Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100193, China.
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22
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Adipose-Derived Stem Cells Alleviate Radiation-Induced Muscular Fibrosis by Suppressing the Expression of TGF-β1. Stem Cells Int 2015; 2016:5638204. [PMID: 26649050 PMCID: PMC4663335 DOI: 10.1155/2016/5638204] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2015] [Revised: 08/12/2015] [Accepted: 08/31/2015] [Indexed: 02/07/2023] Open
Abstract
We aim to investigate the effects of adipose-derived stem cells (ASCs) transplantation on irradiation-induced skeletal muscle fibrosis. Sixty-four rabbits were randomly divided into ASCs group and PBS group followed by irradiation at unilateral hip with a single dose of 80 Gy. Nonirradiated side with normal skeletal muscle served as normal control. Skeletal muscle tissues were collected from eight rabbits in each group at 1 w, 4 w, 8 w, and 26 w after irradiation. Migration of ASCs was observed in the peripheral tissues along the needle passage in the injured muscle. The proportion of the area of collagen fibers to the total area in sections of ASCs group was lower than those of PBS groups at 4 w, 8 w, and 26 w after irradiation. Significant decrease was noted in the integrated optimal density of the transforming growth factor β1 (TGF-β1) in the ASCs group compared with those of PBS group at 4 w, 8 w, and 26 w after irradiation. Moreover, the expression of TGF-β1 was lower in the ASCs group compared to those of the PBS group at each time point determined by Western blot analysis. ASCs transplantation could alleviate irradiation fibrosis by suppressing the level of TGF-β1 in the irradiated skeletal muscle.
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23
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Straub JM, New J, Hamilton CD, Lominska C, Shnayder Y, Thomas SM. Radiation-induced fibrosis: mechanisms and implications for therapy. J Cancer Res Clin Oncol 2015; 141:1985-94. [PMID: 25910988 DOI: 10.1007/s00432-015-1974-6] [Citation(s) in RCA: 422] [Impact Index Per Article: 42.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2015] [Accepted: 04/15/2015] [Indexed: 01/01/2023]
Abstract
PURPOSE Radiation-induced fibrosis (RIF) is a long-term side effect of external beam radiation therapy for the treatment of cancer. It results in a multitude of symptoms that significantly impact quality of life. Understanding the mechanisms of RIF-induced changes is essential to developing effective strategies to prevent long-term disability and discomfort following radiation therapy. In this review, we describe the current understanding of the etiology, clinical presentation, pathogenesis, treatment, and directions of future therapy for this condition. METHODS A literature review of publications describing mechanisms or treatments of RIF was performed. Specific databases utilized included PubMed and clinicaltrials.gov, using keywords "Radiation-Induced Fibrosis," "Radiotherapy Complications," "Fibrosis Therapy," and other closely related terms. RESULTS RIF is the result of a misguided wound healing response. In addition to causing direct DNA damage, ionizing radiation generates reactive oxygen and nitrogen species that lead to localized inflammation. This inflammatory process ultimately evolves into a fibrotic one characterized by increased collagen deposition, poor vascularity, and scarring. Tumor growth factor beta serves as the primary mediator in this response along with a host of other cytokines and growth factors. Current therapies have largely been directed toward these molecular targets and their associated signaling pathways. CONCLUSION Although RIF is widely prevalent among patients undergoing radiation therapy and significantly impacts quality of life, there is still much to learn about its pathogenesis and mechanisms. Current treatments have stemmed from this understanding, and it is anticipated that further elucidation will be essential for the development of more effective therapies.
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Affiliation(s)
- Jeffrey M Straub
- Department of Otolaryngology-Head and Neck Surgery, University of Kansas Medical Center, 3901 Rainbow Boulevard, 3020A Wahl Hall East, Kansas City, KS, 66160, USA
| | - Jacob New
- Department of Anatomy and Cell Biology, University of Kansas Medical Center, Kansas City, KS, 66160, USA
| | - Chase D Hamilton
- Department of Otolaryngology-Head and Neck Surgery, University of Kansas Medical Center, 3901 Rainbow Boulevard, 3020A Wahl Hall East, Kansas City, KS, 66160, USA
| | - Chris Lominska
- Department of Radiation Oncology, University of Kansas Medical Center, Kansas City, KS, 66160, USA
| | - Yelizaveta Shnayder
- Department of Otolaryngology-Head and Neck Surgery, University of Kansas Medical Center, 3901 Rainbow Boulevard, 3020A Wahl Hall East, Kansas City, KS, 66160, USA
| | - Sufi M Thomas
- Department of Otolaryngology-Head and Neck Surgery, University of Kansas Medical Center, 3901 Rainbow Boulevard, 3020A Wahl Hall East, Kansas City, KS, 66160, USA. .,Department of Anatomy and Cell Biology, University of Kansas Medical Center, Kansas City, KS, 66160, USA. .,Department of Cancer Biology, University of Kansas Medical Center, Kansas City, KS, 66160, USA.
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Kreuzer M, Auvinen A, Cardis E, Hall J, Jourdain JR, Laurier D, Little MP, Peters A, Raj K, Russell NS, Tapio S, Zhang W, Gomolka M. Low-dose ionising radiation and cardiovascular diseases – Strategies for molecular epidemiological studies in Europe. MUTATION RESEARCH-REVIEWS IN MUTATION RESEARCH 2015; 764:90-100. [DOI: 10.1016/j.mrrev.2015.03.002] [Citation(s) in RCA: 46] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/02/2014] [Revised: 03/25/2015] [Accepted: 03/26/2015] [Indexed: 12/31/2022]
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25
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Slezak J, Kura B, Ravingerová T, Tribulova N, Okruhlicova L, Barancik M. Mechanisms of cardiac radiation injury and potential preventive approaches. Can J Physiol Pharmacol 2015; 93:737-53. [PMID: 26030720 DOI: 10.1139/cjpp-2015-0006] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
In addition to cytostatic treatment and surgery, the most common cancer treatment is gamma radiation. Despite sophisticated radiological techniques however, in addition to irradiation of the tumor, irradiation of the surrounding healthy tissue also takes place, which results in various side-effects, depending on the absorbed dose of radiation. Radiation either damages the cell DNA directly, or indirectly via the formation of oxygen radicals that in addition to the DNA damage, react with all cell organelles and interfere with their molecular mechanisms. The main features of radiation injury besides DNA damage is inflammation and increased expression of pro-inflammatory genes and cytokines. Endothelial damage and dysfunction of capillaries and small blood vessels plays a particularly important role in radiation injury. This review is focused on summarizing the currently available data concerning the mechanisms of radiation injury, as well as the effectiveness of various antioxidants, anti-inflammatory cytokines, and cytoprotective substances that may be utilized in preventing, mitigating, or treating the toxic effects of ionizing radiation on the heart.
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Affiliation(s)
- Jan Slezak
- Institute for Heart Research, Slovak Academy of Sciences, Dúbravská cesta 9, 842 33 Bratislava, Slovak Republic.,Institute for Heart Research, Slovak Academy of Sciences, Dúbravská cesta 9, 842 33 Bratislava, Slovak Republic
| | - Branislav Kura
- Institute for Heart Research, Slovak Academy of Sciences, Dúbravská cesta 9, 842 33 Bratislava, Slovak Republic.,Institute for Heart Research, Slovak Academy of Sciences, Dúbravská cesta 9, 842 33 Bratislava, Slovak Republic
| | - Táňa Ravingerová
- Institute for Heart Research, Slovak Academy of Sciences, Dúbravská cesta 9, 842 33 Bratislava, Slovak Republic.,Institute for Heart Research, Slovak Academy of Sciences, Dúbravská cesta 9, 842 33 Bratislava, Slovak Republic
| | - Narcisa Tribulova
- Institute for Heart Research, Slovak Academy of Sciences, Dúbravská cesta 9, 842 33 Bratislava, Slovak Republic.,Institute for Heart Research, Slovak Academy of Sciences, Dúbravská cesta 9, 842 33 Bratislava, Slovak Republic
| | - Ludmila Okruhlicova
- Institute for Heart Research, Slovak Academy of Sciences, Dúbravská cesta 9, 842 33 Bratislava, Slovak Republic.,Institute for Heart Research, Slovak Academy of Sciences, Dúbravská cesta 9, 842 33 Bratislava, Slovak Republic
| | - Miroslav Barancik
- Institute for Heart Research, Slovak Academy of Sciences, Dúbravská cesta 9, 842 33 Bratislava, Slovak Republic.,Institute for Heart Research, Slovak Academy of Sciences, Dúbravská cesta 9, 842 33 Bratislava, Slovak Republic
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Cetin E, Ozturk AS, Orhun H, Ulger S. Role of triamcinolone in radiation enteritis management. World J Gastroenterol 2014; 20:4341-4344. [PMID: 24764671 PMCID: PMC3989969 DOI: 10.3748/wjg.v20.i15.4341] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/23/2013] [Accepted: 01/02/2014] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the role of triamcinolone in the management of acute and chronic enteritis caused by pelvic radiotherapy.
METHODS: Twenty-eight patients with rectum adenocarcinoma or endometrium adenocarcinoma were studied. We compared the results of 14 patients treated with injected triamcinolone acetonide (TA) with those of 14 patients who were not treated with TA. For the TA group, 40 mg of TA was injected intramuscularly on the 1st, 11th and 21st d of radiotherapy; the control group received no injections. All of the study participants had a median age of 65 years, had undergone postoperative radiotherapy and were evaluated weekly using Radiation Therapy Oncology Group and the European Organization for Research and Treatment of Cancer Acute Morbidity Score Criteria, and complete blood counts for every 10 d.
RESULTS: Triamcinolone was found to effectively prevent and treat radiation-induced acute gastrointestinal (enteritis) and genitourinary (cystitis) side effects (P = 0.022 and P = 0.023). For the lower GI side effect follow up, 11 patients in the control group had Grade 2 toxicity and 3 patients had Grade 1 toxicity. In the TA group, 5 patients had Grade 2 toxicity and 9 patients had Grade 1 toxicity. For the genitourinary system side effect follow up, 4 patients had Grade 2 toxicity and 6 patients had Grade 1 toxicity. Additionally, 2 patients had Grade 2 toxicity and 2 patients had Grade 1 toxicity. The neutrophil counts did not differ between the TA group and the control group. There was no meaningful difference between age groups and primary cancers. At the 12th mo of follow up, there were no differences between groups for chronic side effects.
CONCLUSION: Triamcinolone is a moderately potent steroid, that is inexpensive and has a good safety profile. It would be beneficial for reducing medical expenses related to treatment of radiation induced enteritis.
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He J, Deng L, Na F, Xue J, Gao H, Lu Y. The association between TGF-β1 polymorphisms and radiation pneumonia in lung cancer patients treated with definitive radiotherapy: a meta-analysis. PLoS One 2014; 9:e91100. [PMID: 24642488 PMCID: PMC3958356 DOI: 10.1371/journal.pone.0091100] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2013] [Accepted: 02/07/2014] [Indexed: 02/05/2023] Open
Abstract
Background Previous studies investigating the association between TGF-β1 polymorphisms and Radiation Pneumonia (RP) risk have provided inconsistent results. The aim of our study was to assess the association between the TGF-β1 genes C509T, G915C and T869C polymorphisms and risk of RP in lung cancer patients treated with definitive radiotherapy. Methods Two investigators independently searched the Medline, Embase, CNKI, and Chinese Biomedicine Databases for studies published before September 2013. Summary odds ratios (ORs) and 95% confidence intervals (CIs) for TGF-β1 polymorphisms and RP were calculated in a fixed-effects model or a random-effects model when appropriate. Results Ultimately, each 7 studies were found to be eligible for meta-analyses of C509T, G915C and T869C, respectively. Our analysis suggested that the variant genotypes of T869C were associated with a significantly increased RP risk in dominant model (OR = 0.59, 95% CI = 0.45–0.79) and CT vs. TT model (OR = 0.47, 95% CI = 0.32–0.69). In the subgroup analyses by ethnicity/country, a significantly increased risk was observed among Caucasians. For C509T and G915C polymorphism, no obvious associations were found for all genetic models. Conclusion This meta-analysis suggests that T869C polymorphism of TGF-β1 may be associated with RP risk only in Caucasians, and there may be no association between C509T and G915C polymorphism and RP risk.
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Affiliation(s)
- Jiazhuo He
- Department of Thoracic Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, PR China
| | - Lei Deng
- Department of Thoracic Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, PR China
| | - Feifei Na
- Department of Thoracic Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, PR China
| | - Jianxin Xue
- Department of Thoracic Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, PR China
| | - Hui Gao
- Department of Thoracic Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, PR China
| | - You Lu
- Department of Thoracic Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, PR China
- * E-mail:
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Bira Y, Tani K, Nishioka Y, Miyata J, Sato K, Hayashi A, Nakaya Y, Sone S. Transforming growth factor β stimulates rheumatoid synovial fibroblasts via the type II receptor. Mod Rheumatol 2014. [DOI: 10.3109/s10165-004-0378-2] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
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Radio-induced apoptosis of peripheral blood CD8 T lymphocytes is a novel prognostic factor for survival in cervical carcinoma patients. Strahlenther Onkol 2013; 190:210-6. [PMID: 24362501 DOI: 10.1007/s00066-013-0488-x] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2013] [Accepted: 10/18/2013] [Indexed: 01/01/2023]
Abstract
BACKGROUND AND PURPOSE A close relationship exists between immune response and tumor behavior. This study aimed to explore the associations between radiation-induced apoptosis (RIA) in peripheral blood lymphocytes (PBL) and clinical pathological variables. Furthermore, it assessed the role of RIA as a prognostic factor for survival in cervical carcinoma patients. PATIENTS AND METHODS Between February 1998 and October 2003, 58 consecutive patients with nonmetastatic, localized stage I-II cervical carcinoma who had been treated with radiotherapy (RT) ± chemotherapy were included in this study. Follow-up ended in January 2013. PBL subpopulations were isolated and irradiated with 0, 1, 2 and 8 Gy then incubated for 24, 48 and 72 h. Apoptosis was measured by flow cytometry and the β value, a parameter defining RIA of lymphocytes, was calculated. RESULTS Mean follow-up duration was 111.92 ± 40.31 months. Patients with lower CD8 T lymphocyte β values were at a higher risk of local relapse: Exp(B) = 5.137, confidence interval (CI) 95 % = 1.044-25.268, p = 0.044. Similar results were observed for regional relapse: Exp(B) = 8.008, CI 95 % = 1.702-37.679, p = 0.008 and disease relapse: Exp(B) = 6.766, CI 95 % = 1.889-24.238, p = 0.003. In multivariate analysis, only the CD8 T lymphocyte β values were found to be of prognostic significance for local disease-free survival (LDFS, p = 0.049), regional disease-free survival (RDFS, p = 0.002), metastasis-free survival (MFS, p = 0.042), disease-free survival (DFS, p = 0.001) and cause-specific survival (CSS p = 0.028). CONCLUSION For the first time, RIA in CD8 T lymphocytes was demonstrated to be a predictive factor for survival in cervical carcinoma patients.
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Stewart FA, Seemann I, Hoving S, Russell NS. Understanding radiation-induced cardiovascular damage and strategies for intervention. Clin Oncol (R Coll Radiol) 2013; 25:617-24. [PMID: 23876528 DOI: 10.1016/j.clon.2013.06.012] [Citation(s) in RCA: 100] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2013] [Revised: 04/26/2013] [Accepted: 06/30/2013] [Indexed: 12/22/2022]
Abstract
There is a clear association between therapeutic doses of thoracic irradiation and an increased risk of cardiovascular disease (CVD) in cancer survivors, although these effects may take decades to become symptomatic. Long-term survivors of Hodgkin's lymphoma and childhood cancers have two-fold to more than seven-fold increased risks for late cardiac deaths after total tumour doses of 30-40 Gy, given in 2 Gy fractions, where large volumes of heart were included in the field. Increased cardiac mortality is also seen in women irradiated for breast cancer. Breast doses are generally 40-50 Gy in 2 Gy fractions, but only a small part of the heart is included in the treatment fields and mean heart doses rarely exceeded 10-15 Gy, even with older techniques. The relative risks of cardiac mortality (1.1-1.4) are consequently lower than for Hodgkin's lymphoma survivors. Some epidemiological studies show increased risks of cardiac death after accidental or environmental total body exposures to much lower radiation doses. The mechanisms whereby these cardiac effects occur are not fully understood and different mechanisms are probably involved after high therapeutic doses to the heart, or part of the heart, than after low total body exposures. These various mechanisms probably result in different cardiac pathologies, e.g. coronary artery atherosclerosis leading to myocardial infarct, versus microvascular damage and fibrosis leading to congestive heart failure. Experimental studies can help to unravel some of these mechanisms and may identify suitable strategies for managing or inhibiting CVD. In this overview, the main epidemiological and clinical evidence for radiation-induced CVD is summarised. Experimental data shedding light on some of the underlying pathologies and possible targets for intervention are also discussed.
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Affiliation(s)
- F A Stewart
- Division of Biological Stress Response, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
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Schaue D, Kachikwu EL, McBride WH. Cytokines in radiobiological responses: a review. Radiat Res 2012; 178:505-23. [PMID: 23106210 DOI: 10.1667/rr3031.1] [Citation(s) in RCA: 279] [Impact Index Per Article: 21.5] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Cytokines function in many roles that are highly relevant to radiation research. This review focuses on how cytokines are structurally organized, how they are induced by radiation, and how they orchestrate mesenchymal, epithelial and immune cell interactions in irradiated tissues. Pro-inflammatory cytokines are the major components of immediate early gene programs and as such can be rapidly activated after tissue irradiation. They converge with the effects of ionizing radiation in that both generate free radicals including reactive oxygen and nitrogen species (ROS/RNS). "Self" molecules secreted or released from cells after irradiation feed the same paradigm by signaling for ROS and cytokine production. As a result, multilayered feedback control circuits can be generated that perpetuate the radiation tissue damage response. The pro-inflammatory phase persists until such times as perceived challenges to host integrity are eliminated. Antioxidant, anti-inflammatory cytokines then act to restore homeostasis. The balance between pro-inflammatory and anti-inflammatory forces may shift to and fro for a long time after radiation exposure, creating waves as the host tries to deal with persisting pathogenesis. Individual cytokines function within socially interconnected groups to direct these integrated cellular responses. They hunt in packs and form complex cytokine networks that are nested within each other so as to form mutually reinforcing or antagonistic forces. This yin-yang balance appears to have redox as a fulcrum. Because of their social organization, cytokines appear to have a considerable degree of redundancy and it follows that an elevated level of a specific cytokine in a disease situation or after irradiation does not necessarily implicate it causally in pathogenesis. In spite of this, "driver" cytokines are emerging in pathogenic situations that can clearly be targeted for therapeutic benefit, including in radiation settings. Cytokines can greatly affect intrinsic cellular radiosensitivity, the incidence and type of radiation tissue complications, bystander effects, genomic instability and cancer. Minor and not so minor, polymorphisms in cytokine genes give considerable diversity within populations and are relevant to causation of disease. Therapeutic intervention is made difficult by such complexity; but the potential prize is great.
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Affiliation(s)
- Dörthe Schaue
- David Geffen School Medicine, University of California at Los Angeles, Los Angeles, California 90095-1714, USA.
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Zaidi A, Jelveh S, Mahmood J, Hill RP. Effects of lipopolysaccharide on the response of C57BL/6J mice to whole thorax irradiation. Radiother Oncol 2012; 105:341-9. [PMID: 22985778 DOI: 10.1016/j.radonc.2012.08.003] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2012] [Revised: 06/28/2012] [Accepted: 08/11/2012] [Indexed: 01/15/2023]
Abstract
BACKGROUND AND PURPOSE Inflammatory and fibrogenic processes play a crucial role in the radiation-induced injury in the lung. The aim of the present study was to examine whether additive LPS exposure in the lung (to simulate respiratory infection) would affect pneumonitis or fibrosis associated with lung irradiation. MATERIAL AND METHODS Wildtype C57Bl/6J (WT-C57) and TNFα, TNFR1 and TNFR2 knockout ((-/-)) mice, in C57Bl/6J background, were given whole thorax irradiation (10 Gy) with or without post-irradiation intratracheal administration of LPS (50μg/mice). Functional deficit was examined by measuring breathing rate at various times after treatment. Real-time Reverse Transcription-Polymerase Chain Reaction (RT-PCR) and immunohistochemistry were used to analyze the protein expression and m-RNA of Interleukin-1 alpha (IL-1α), Interleukin-1 beta (IL-1β), Interleukin-6 (IL-6), Tumour Necrosis Factor alpha (TNFα) and Transforming Growth Factor beta (TGFβ) in the lung at various times after treatment. Inflammatory cells were detected by Mac-3 (macrophages) and Toluidine Blue (mast cells) staining. Collagen content was estimated by hydroxyproline (total collagen) and Sircol assay (soluble collagen). Levels of oxidative damage were assessed by 8-hydroxy-2-deoxyguanosine (8-OHdG) staining. RESULTS LPS exposure significantly attenuated the breathing rate increases following irradiation of WT-C57, TNFR1(-/-) and TNFR2(-/-)mice and to a lesser extent in TNFα(-/-) mice. Collagen content was significantly reduced after LPS treatment in WT-C57, TNFR1(-/-) and TNFα(-/-) mice and there was a trend in TNFR2(-/-) mice. Similarly there were lower levels of inflammatory cells and cytokines in the LPS treated mice. CONCLUSIONS This study reveals a mitigating effect of early exposure to LPS on injury caused by irradiation on lungs of C57Bl mice. The results suggest that immediate infection post irradiation may not impact lung response negatively in radiation-accident victims, however, further studies are required in different animal models, and with specific infectious agents, to confirm and extend our findings.
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Affiliation(s)
- Asif Zaidi
- Ontario Cancer Institute, Toronto, Ontario, Canada
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Wessels Q, Pretorius E, Smith CM, Nel H. The potential of a niacinamide dominated cosmeceutical formulation on fibroblast activity and wound healing in vitro. Int Wound J 2012; 11:152-8. [PMID: 22892041 DOI: 10.1111/j.1742-481x.2012.01052.x] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023] Open
Abstract
Knowledge on the intrinsic mechanisms involved in wound healing provides opportunity for various therapeutic strategies. The manipulation of dermal fibroblast proliferation and differentiation might prove to beneficially augment wound healing. This study evaluated the combined effects of niacinamide, L-carnosine, hesperidin and Biofactor HSP(®) on fibroblast activity. The effects on fibroblast collagen production, cellular proliferation, migration and terminal differentiation were assessed. In addition, the authors determined the effects on in vitro wound healing. The optimal concentrations of actives were determined in vitro. Testing parameters included microscopic morphological cell analysis, cell viability and proliferation determination, calorimetric collagen detection and in vitro wound healing dynamics. Results show that 0·31 mg/ml niacinamide, 0·10 mg/ml L-carnosine, 0·05 mg/ml hesperidin and 5·18 µg/ml Biofactor HSP® proved optimal in vitro. The results show that fibroblast collagen synthesis was increased alongside with cellular migration and proliferation.
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Affiliation(s)
- Quenton Wessels
- Department of Anatomy, School of Medicine, University of Namibia, Windhoek, NamibiaDepartment of Physiology, School of Medicine, Faculty of Health Sciences, University of Pretoria, South AfricaSouthern group of Companies, Southern Implants Office Park, Irene, South Africa
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Sardaro A, Petruzzelli MF, D'Errico MP, Grimaldi L, Pili G, Portaluri M. Radiation-induced cardiac damage in early left breast cancer patients: risk factors, biological mechanisms, radiobiology, and dosimetric constraints. Radiother Oncol 2012; 103:133-42. [PMID: 22391054 DOI: 10.1016/j.radonc.2012.02.008] [Citation(s) in RCA: 149] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2011] [Revised: 01/30/2012] [Accepted: 02/04/2012] [Indexed: 01/29/2023]
Abstract
Today there is general awareness of the potential damage to the heart in left-sided (more than in right-sided) breast cancer radiotherapy (RT). Historical changes in tumor and heart doses are presented here along with the impact of different RT techniques and volumes. Individual and pharmacological risk factors are also examined with respect to radiation damage. The biological mechanisms of harm are only partially understood, such as the radiobiology of heart damage due to the presence of various radiosensitive structures and their topographic heterogeneity. Furthermore, individual variability may expose patients to higher or lower risks of late cardiac damage or death. Damage mechanisms and radiobiological characteristics in heart irradiation are presented in relation to dosimetric and biological parameters.
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Affiliation(s)
- Angela Sardaro
- University Institute of Radiation Oncology Policlinico di Bari, Italy
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Stewart FA, Akleyev AV, Hauer-Jensen M, Hendry JH, Kleiman NJ, Macvittie TJ, Aleman BM, Edgar AB, Mabuchi K, Muirhead CR, Shore RE, Wallace WH. ICRP publication 118: ICRP statement on tissue reactions and early and late effects of radiation in normal tissues and organs--threshold doses for tissue reactions in a radiation protection context. Ann ICRP 2012; 41:1-322. [PMID: 22925378 DOI: 10.1016/j.icrp.2012.02.001] [Citation(s) in RCA: 856] [Impact Index Per Article: 65.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/03/2023]
Abstract
This report provides a review of early and late effects of radiation in normal tissues and organs with respect to radiation protection. It was instigated following a recommendation in Publication 103 (ICRP, 2007), and it provides updated estimates of 'practical' threshold doses for tissue injury defined at the level of 1% incidence. Estimates are given for morbidity and mortality endpoints in all organ systems following acute, fractionated, or chronic exposure. The organ systems comprise the haematopoietic, immune, reproductive, circulatory, respiratory, musculoskeletal, endocrine, and nervous systems; the digestive and urinary tracts; the skin; and the eye. Particular attention is paid to circulatory disease and cataracts because of recent evidence of higher incidences of injury than expected after lower doses; hence, threshold doses appear to be lower than previously considered. This is largely because of the increasing incidences with increasing times after exposure. In the context of protection, it is the threshold doses for very long follow-up times that are the most relevant for workers and the public; for example, the atomic bomb survivors with 40-50years of follow-up. Radiotherapy data generally apply for shorter follow-up times because of competing causes of death in cancer patients, and hence the risks of radiation-induced circulatory disease at those earlier times are lower. A variety of biological response modifiers have been used to help reduce late reactions in many tissues. These include antioxidants, radical scavengers, inhibitors of apoptosis, anti-inflammatory drugs, angiotensin-converting enzyme inhibitors, growth factors, and cytokines. In many cases, these give dose modification factors of 1.1-1.2, and in a few cases 1.5-2, indicating the potential for increasing threshold doses in known exposure cases. In contrast, there are agents that enhance radiation responses, notably other cytotoxic agents such as antimetabolites, alkylating agents, anti-angiogenic drugs, and antibiotics, as well as genetic and comorbidity factors. Most tissues show a sparing effect of dose fractionation, so that total doses for a given endpoint are higher if the dose is fractionated rather than when given as a single dose. However, for reactions manifesting very late after low total doses, particularly for cataracts and circulatory disease, it appears that the rate of dose delivery does not modify the low incidence. This implies that the injury in these cases and at these low dose levels is caused by single-hit irreparable-type events. For these two tissues, a threshold dose of 0.5Gy is proposed herein for practical purposes, irrespective of the rate of dose delivery, and future studies may elucidate this judgement further.
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Zhuang Q, Zhang Z, Fu H, He J, He Y. Does radiation-induced fibrosis have an important role in pathophysiology of the osteoradionecrosis of jaw? Med Hypotheses 2011; 77:63-5. [DOI: 10.1016/j.mehy.2011.03.024] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2010] [Revised: 02/18/2011] [Accepted: 03/12/2011] [Indexed: 02/05/2023]
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Rocha BR, Gombar FM, Barcellos LM, Costa WS, Barcellos Sampaio FJ, Ramos CF. Glutamine supplementation prevents collagen expression damage in healthy urinary bladder caused by radiotherapy. Nutrition 2011; 27:809-15. [DOI: 10.1016/j.nut.2010.07.020] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2010] [Revised: 07/19/2010] [Accepted: 07/30/2010] [Indexed: 11/28/2022]
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Wernicke AG, Parashar B, Kulidzhanov F, Riley L, Christos PJ, Fischer A, Nori D, Chao KSC. Prospective study validating inter- and intraobserver variability of tissue compliance meter in breast tissue of healthy volunteers: potential implications for patients with radiation-induced fibrosis of the breast. Int J Radiat Oncol Biol Phys 2011; 80:39-46. [PMID: 20395064 PMCID: PMC3612398 DOI: 10.1016/j.ijrobp.2010.01.064] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2009] [Revised: 12/04/2009] [Accepted: 01/19/2010] [Indexed: 12/25/2022]
Abstract
PURPOSE Accurate detection of radiation-induced fibrosis (RIF) is crucial in management of breast cancer survivors. Tissue compliance meter (TCM) has been validated in musculature. We validate TCM in healthy breast tissue with respect to interobserver and intraobserver variability before applying it in RIF. METHODS AND MATERIALS Three medical professionals obtained three consecutive TCM measurements in each of the four quadrants of the right and left breasts of 40 women with no breast disease or surgical intervention. The intraclass correlation coefficient (ICC) assessed interobserver variability. The paired t test and Pearson correlation coefficient (r) were used to assess intraobserver variability within each rater. RESULTS The median age was 45 years (range, 24-68 years). The median bra size was 35C (range, 32A-40DD). Of the participants, 27 were white (67%), 4 black (10%), 5 Asian (13%), and 4 Hispanic (10%). ICCs indicated excellent interrater reliability (low interobserver variability) among the three raters, by breast and quadrant (all ICC ≥ 0.99). The paired t test and Pearson correlation coefficient both indicated low intraobserver variability within each rater (right vs. left breast), stratified by quadrant (all r ≥ 0.94, p < 0.0001). CONCLUSIONS The interobserver and intraobserver variability is small using TCM in healthy mammary tissue. We are now embarking on a prospective study using TCM in women with breast cancer at risk of developing RIF that may guide early detection, timely therapeutic intervention, and assessment of success of therapy for RIF.
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Affiliation(s)
- A Gabriella Wernicke
- Stich Radiation Oncology, Weill Cornell Medical College of Cornell University, New York, NY 10065, USA.
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Qayyum MA, Insana MF. Effects of radiotherapy fractionation on breast stromal activity. ANNUAL INTERNATIONAL CONFERENCE OF THE IEEE ENGINEERING IN MEDICINE AND BIOLOGY SOCIETY. IEEE ENGINEERING IN MEDICINE AND BIOLOGY SOCIETY. ANNUAL INTERNATIONAL CONFERENCE 2011; 2011:282-285. [PMID: 22254304 DOI: 10.1109/iembs.2011.6090074] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/31/2023]
Abstract
We study the dynamics of tumor cell progression as growth factors and ionizing radiation (IR) combine to modify cellular microenvironments. Breast tumor growth depends on the behavior of cancer cells in their microenvironment, and both components are affected by IR fractionation parameters. TGF-β1 promotes differentiation of fibroblasts to myofibroblasts, which stiffens the extracellular matrix (ECM) and promotes malignant cell phenotypes. IR generates reactive oxygen species (ROS) that damages and inactivates cells thus controlling proliferation. The effects of TGF-β1 and IR at various fraction sizes on ECM stiffness and fibroblast differenation are studied using MRC-5 fibroblasts in 3-D collagen cultures.
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Affiliation(s)
- Muqeem A Qayyum
- Departments of Bioengineering and Nuclear and Beckman Institute for Advanced Science and Technology, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA.
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Abstract
Thromboembolic complications are the second leading cause of death in cancer patients. In contrast to the large body of literature on venous thromboembolism (VTE), relatively few reports have focused on the pathogenesis, incidence, management and outcomes of arterial thromboembolic events in patients with malignancy. The purpose of this article is to review the current literature on the etiology, mechanisms, and prognosis of arterial thromboembolic events in cancer patients and outline appropriate screening and management guidelines that may help lower the rates of morbidity and mortality related to these events.
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Affiliation(s)
- Saurabh Sanon
- Department of Internal Medicine, The University of Texas Health Science Center at Houston, Houston, TX, USA
| | - Daniel J Lenihan
- Division of Cardiovascular Medicine, Vanderbilt University, Nashville, TN, USA
| | - Elie Mouhayar
- Division of Internal Medicine, Department of Cardiology, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA,
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Abstract
Radiation leaves a fairly characteristic footprint in biological materials, but this is rapidly all but obliterated by the canonical biological responses to the radiation damage. The innate immune recognition systems that sense "danger" through direct radiation damage and through associated collateral damage set in motion a chain of events that, in a tissue compromised by radiation, often unwittingly result in oscillating waves of molecular and cellular responses as tissues attempt to heal. Understanding "nature's whispers" that inform on these processes will lead to novel forms of intervention targeted more precisely towards modifying them in an appropriate and timely fashion so as to improve the healing process and prevent or mitigate the development of acute and late effects of normal tissue radiation damage, whether it be accidental, as a result of a terrorist incident, or of therapeutic treatment of cancer. Here we attempt to discuss some of the non-free radical scavenging mechanisms that modify radiation responses and comment on where we see them within a conceptual framework of an evolving radiation-induced lesion.
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Affiliation(s)
- Kwanghee Kim
- Department of Radiation Oncology, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, California 90095, USA
| | - William H. McBride
- Department of Radiation Oncology, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, California 90095, USA
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Akleyev AV. Tissue reactions under chronic exposure to ionizing radiation. Biophysics (Nagoya-shi) 2010. [DOI: 10.1134/s0006350910010203] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022] Open
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Wernicke AG, Rosenblatt R, Rasca M, Parhar P, Christos PJ, Fischer A, Parashar B, Nori D. Quantitative Assessment of Radiation-Induced Fibrosis of the Breast with Tissue Compliance Meter, Palpation, and Radiological Imaging: Preliminary Results. Breast J 2009; 15:583-92. [DOI: 10.1111/j.1524-4741.2009.00835.x] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
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Effects of genistein following fractionated lung irradiation in mice. Radiother Oncol 2009; 92:500-10. [DOI: 10.1016/j.radonc.2009.04.005] [Citation(s) in RCA: 52] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2008] [Revised: 03/07/2009] [Accepted: 04/06/2009] [Indexed: 11/18/2022]
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Johnston CJ, Williams JP, Elder A, Hernady E, Finkelstein JN. INFLAMMATORY CELL RECRUITMENT FOLLOWING THORACIC IRRADIATION. Exp Lung Res 2009; 30:369-82. [PMID: 15204829 DOI: 10.1080/01902140490438915] [Citation(s) in RCA: 72] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/26/2022]
Abstract
Ionizing radiation leads to a progressive injury in which a monocyte/macrophage-rich pneumonitis is followed by a chronic progressive fibrosis. In the present study, the role of macrophage/monocyte recruitment in the genesis of radiation-induced pulmonary fibrosis was examined. The objectives were threefold: (i) characterize the inflammatory cells recruited into the lung during the development of radiation-induced fibrosis; (ii) investigate changes in lung response following depletion of resident alveolar macrophages in vivo prior to radiation treatment; (iii) assess if inhalation of low levels of endotoxin would potentiate the radiation-initiated injury. One group of fibrosis-sensitive C57BL/6 mice was irradiated with a single dose of 15 Gy to the thorax. In a second group, resident inflammatory cells were depleted using clodronate, encapsulated into liposomes, 48 hours prior to irradiation with a single dose of 15 Gy to the thorax. Control animals were sham irradiated. All groups of animals then were examined 8, 16, or 24 weeks post irradiation. No difference in total cell numbers or cell differentials was observed between irradiated mice or those that were both liposome treated and irradiated at any time point. At 16 weeks, mice that received radiation showed a 5- to 6-fold increase in lymphocytes regardless of treatment as compared to control animals. At 24 weeks post irradiation, select groups were exposed to lipopolysaccharide (LPS) and examined 24 hours post inhalation. Lavageable protein was increased several fold in mice that received both radiation and LPS exposure as compared to 15 Gy or LPS exposure alone. These results demonstrate: (i) macrophages and lymphocytes are the predominately recruited cell types through 24 weeks post irradiation; (ii) recovery of inflammatory cells, regardless of prior macrophage depletion, were similar, suggesting that early responses are primarily driven by parenchymal cell injury; (iii) thoracic irradiation-induced injury can cause sensitization to a secondary stimulus that may result in injuries/responses not predicted by evaluating exposures individually.
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Affiliation(s)
- Carl J Johnston
- Department of Environmental Medicine, University of Rochester, New York 14642, USA
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Horgan N, Shields CL, Mashayekhi A, Salazar PF, Materin MA, O'Regan M, Shields JA. Periocular triamcinolone for prevention of macular edema after plaque radiotherapy of uveal melanoma: a randomized controlled trial. Ophthalmology 2009; 116:1383-90. [PMID: 19481812 DOI: 10.1016/j.ophtha.2009.01.051] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2008] [Revised: 01/01/2009] [Accepted: 01/28/2009] [Indexed: 12/15/2022] Open
Abstract
OBJECTIVE To determine the efficacy and safety of periocular triamcinolone acetonide (40 mg) for the prevention of macular edema in patients undergoing plaque radiotherapy for uveal melanoma. DESIGN Prospective, randomized, controlled clinical trial. PARTICIPANTS AND CONTROLS One-hundred sixty-three patients with newly diagnosed uveal melanoma undergoing iodine 125 plaque radiotherapy were entered into the study. Fifty-five patients were randomized to the control group and 108 to the triamcinolone group. Eighteen-month data were available for 143 (88%) of the 163 patients. INTERVENTION Periocular injection of triamcinolone acetonide (40 mg in 1 ml) at the time of plaque radiotherapy and 4 months and 8 months later. Optical coherence tomography was performed at each patient evaluation. MAIN OUTCOME MEASURES Optical coherence tomography-evident macular edema, moderate vision loss, and poor final visual acuity. RESULTS Optical coherence tomography-evident macular edema occurred significantly less often in the triamcinolone group compared with the control group up to 18 months after plaque radiotherapy (hazard estimate, 0.45; 95% confidence interval, 0.19-0.70; P = 0.001). At the 18-month follow-up, moderate vision loss (loss of 3 lines or more of best-corrected visual acuity [BCVA]) and severe vision loss (BCVA <5/200 Snellen) occurred significantly less frequently in the triamcinolone group than in the control group (31% vs. 48% [P = 0.039] and 5% vs. 15% [P = 0.048], respectively). Rates of elevated intraocular pressure and cataract progression were similar in both groups. CONCLUSIONS Periocular triamcinolone is beneficial in reducing the risk of macular edema up to 18 months after plaque radiotherapy for uveal melanoma and significantly reduces the risk of moderate vision loss and poor visual acuity in these patients.
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Affiliation(s)
- Noel Horgan
- Ocular Oncology Service, Wills Eye Institute, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA
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Park KJ, Oh YT, Kil WJ, Park W, Kang SH, Chun M. Bronchoalveolar lavage findings of radiation induced lung damage in rats. JOURNAL OF RADIATION RESEARCH 2009; 50:177-182. [PMID: 19377267 DOI: 10.1269/jrr.08089] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/27/2023]
Abstract
Radiation induced lung damage is a main dose limiting factor when irradiating the thorax. Although Bronchoalveolar lavage (BAL) is a valuable tool for studying the mechanisms in pulmonary disorders, there are only a few studies about the BAL findings of radiation-induced lung damage. We evaluate the BAL findings for the evaluation of radiation-induced lung damage. Sprague-Dawley rats received 20 Gy of radiation to the right lung and control group were sham irradiated. BAL was performed for the right and left lungs separately 3, 7, 14, 28, and 56 days after radiation. The cells in the BAL fluid were counted and the concentrations of protein, NO, and TGF-beta in the BAL fluid were measured. Lung tissues were removed after BAL and stained with hematoxylin-eosin (H-E) and trichrome. From 2 weeks, histological findings showed definite lung damage. The protein level and TGF-beta in BAL fluid from the irradiated lung peaked at 4 and 8 weeks, respectively, after radiation. Total cell count in BAL fluid from both sides of lungs was increased from 2 weeks and continued to increase at 8 weeks after irradiation. NO in BAL fluid from both sides of lungs peaked at 4 weeks after irradiation. The protein level and TGF-beta were increased in BAL fluid from irradiated lungs. However, alveolar cells and NO increased in BAL fluid from both irradiated and non-irradiated lungs. BAL is a valuable tool for the evaluation of radiation induced lung damage.
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Affiliation(s)
- Kwang-Joo Park
- Department of Radiation Oncology, Pulmononary Medicine, Ajou University School of Medicine, Suwon, Korea
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Liu Y, Kudo K, Abe Y, Hu DL, Kijima H, Nakane A, Ono K. Inhibition of transforming growth factor-beta, hypoxia-inducible factor-1alpha and vascular endothelial growth factor reduced late rectal injury induced by irradiation. JOURNAL OF RADIATION RESEARCH 2009; 50:233-239. [PMID: 19346676 DOI: 10.1269/jrr.08112] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/27/2023]
Abstract
Tumor hypoxia and angiogenesis associated with malignant progression have been studied widely. The efficacy of angiogenesis inhibition combined with radiotherapy has been demonstrated in cancer treatment. Here, we studied the effect of hypoxia and angiogenesis inhibition on radiation-induced late rectal injury. The rectum of C57BL/6N mice was irradiated locally with a single dose of 25 Gy. Radiation-induced histological changes were examined at 90 days after irradiation by hematoxylin-eosin (H.E.) staining and azan staining. Pimonidazole was administered and its distribution was assayed by immunohistochemistry staining. Expression of transforming growth factor beta1 (TGF-beta1), hypoxia-inducible factor-1alpha (HIF-1alpha) and vascular endothelial growth factor (VEGF) was assessed on the fibrotic region using real-time PCR and immunohistochemistry. In addition, the effects of TGF-beta, VEGF and HIF-1alpha on radiation-induced injury were investigated by the administration of neutralizing antibody of TGF-beta, antibody of VEGF or YC-1 (3-(5'-hydroxymethyl-2'-furyl)-1-benzylindazole) which was developed as an agent for inhibiting HIF-1 expression after irradiation respectively. Fibrosis and uptake of pimonidazole were found 90 days after irradiation. The expression of TGF-beta1, HIF-1alpha and VEGF significantly increased with the formation of fibrosis induced by irradiation compared with unirradiated controls. In addition, treatment of neutralizing antibody of TGF-beta, antibody of VEGF or YC-1 reduced the development of radiation-induced injury. Our results suggested that radiation-induced hypoxia may play an important role in late rectal injury. Although the inhibition of HIF-1alpha and VEGF reduced the radiation induced late injury, the precise mechanism is still unclear.
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Affiliation(s)
- Yong Liu
- Departments of Radiology and Radiation Oncology, Hirosaki University, Hirosaki, Japan
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Effect of infliximab on the levels of TNF-alpha and TGF-beta in the whole blood cultures of irradiated patients. Folia Histochem Cytobiol 2008; 46:291-7. [PMID: 19056532 DOI: 10.2478/v10042-008-0050-3] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
TGF-beta is supposed to be the major cytokine responsible for post-radiation fibrosis of healthy tissues and actively modifies post-radiation changes. The growth of TGF-beta level induces the expression of collagen synthesis gene which triggers off the production of fibrosis of hyaline membranes. The main purpose of this study was to discover the way and methods of reducing post-radiation damage of normal tissues and provide an adequate scientific justification for using Infliximab as an effective radio protector in the neoplasm radiotherapy. A group of 97 patients were subjected to the experiment. Randomly selected patients were assigned to 3 groups according to the radiation exposure. The samples of whole blood were suspended in RPMI 1640 growth medium standardized according to the number of leukocytes. Two milliliters of whole blood was taken from each patient immediately before irradiation and 100 microl sample of the blood was placed in wells with 0.8 mg/ml of Infliximab or without the preparation. TGF-beta levels in blood culture without cA2 before irradiation showed continuous rise from 3978 to 8950 pg/ml at the 96th h. In the post irradiated group without cA2, a continuous growth was recorded till the 48th h (from 4758 to 13324 pg/ml at the 24th h) and then a slight decline to 11950 pg/ml at 96th h, respectively. In the cultures with cA2, TGF-beta levels before irradiation showed also the peak value at the 48th h (from 4050 to 7340 pg/ml at the 48th h) and then started to go down (6500 pg/ml at the 72nd h and 5720 pg/ml at the 96th h). In the post-irradiated group, during the first 6 hours, there was a growth from 4717 pg/ml to 7462 pg/ml, and then a paradoxical increase to 16885 pg/ml at the 12th h. From the 12th h the values started to decrease to 6895 pg/ml at the 96th h. The obtained results confirmed the hypothesis of decreasing the TGF-beta expression by inactivating TNF-alpha with a monoclonal antibody (Infliximab) in the patients' whole blood culture in vitro. These observations are a good starting point for further experiments in vitro and in vivo, whose main objective is to reduce post radiation fibrosis.
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Liu Y, Yu H, Zhang C, Cheng Y, Hu L, Meng X, Zhao Y. Protective effects of berberine on radiation-induced lung injury via intercellular adhesion molecular-1 and transforming growth factor-beta-1 in patients with lung cancer. Eur J Cancer 2008; 44:2425-32. [PMID: 18789680 DOI: 10.1016/j.ejca.2008.07.040] [Citation(s) in RCA: 44] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2008] [Revised: 07/19/2008] [Accepted: 07/24/2008] [Indexed: 01/06/2023]
Abstract
PURPOSE To investigate the protective effects of berberine on radiation-induced lung injury (RILI) in non-small cell lung cancer (NSCLC) patients treated with radiotherapy. PATIENTS AND METHODS In this randomised, double-blind study, 90 patients with NSCLC were divided into two groups. The trial group received radiation therapy plus berberine, and the control group received radiation therapy plus a placebo for 6 weeks. Soluble intercellular adhesion molecular-1 (sICAM-1) and transforming growth factor-beta-1 (TGF-beta1) were measured. RILI and pulmonary function were evaluated at 6 weeks and 6 months after treatment, respectively. RESULTS Of the 90 patients enroled, 43 in the control group and 42 in the trial group completed the study. The incidence of RILI was significantly lower in the trial group at 6 weeks and 6 months than that in the control group (45.2% versus 72.1% and 35.7% versus 65.1%, respectively, both P<0.05). sICAM-1 levels in the trial group were significantly lower at weeks 6 and 12 (373.64+/-89.33 versus 459.53+/-123.59 and 447.83+/-111.21 versus 513.91+/-150.46, both P<0.01), and plasma TGF-beta1 levels were lower at week 3 and 6 (5.43+/-1.47 versus 6.22+/-1.78 and 5.93+/-2.39 versus 7.67+/-2.74, P<0.05 and 0.01, respectively) in comparison with the control group. Significant differences were observed in FEV1 (P=0.033) and DLCO (P=0.003) between patients receiving berberine and those receiving placebo. Independent-samples T-test showed reductions from baseline FVC at week 6 (P<0.05), and FEV1 and DLCO at month 6 (P<0.05 and 0.01, respectively) in the trial group were significantly smaller than that in the control group. CONCLUSION Berberine significantly reduced the incidence of RILI, improved PF and decreased the levels of sICAM-1 and TGF-beta1. The exact mechanisms remain to be further explored.
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Affiliation(s)
- Yunfang Liu
- The Key Laboratory of Cardiovascular Remodeling and Function Research, Shandong University, Qilu Hospital, Jinan, Shandong Province, China.
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