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Bouzaki A, Green D, van Herk M, Shortall J, Puri T, Kerns S, Azria D, Farcy-Jacquet MP, Chang-Claude J, Choudhury A, Dunning A, Lambrecht M, Avuzzi B, Ruysscher DD, Seibold P, Sperk E, Talbot C, Vega A, Veldeman L, Webb A, Rosenstein B, West CM, Gioscio E, Rancati T, Osorio EV, McWilliam A. New rectum dose surface mapping methodology to identify rectal subregions associated with toxicities following prostate cancer radiotherapy. Phys Imaging Radiat Oncol 2025; 33:100701. [PMID: 39927213 PMCID: PMC11803856 DOI: 10.1016/j.phro.2025.100701] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2024] [Revised: 01/09/2025] [Accepted: 01/14/2025] [Indexed: 02/11/2025] Open
Abstract
Background and purpose Growing evidence suggests that spatial dose variations across the rectal surface influence toxicity risk after radiotherapy. Existing methodologies employ a fixed, arbitrary physical extent for rectal dose mapping, limiting their analysis. We developed a method to standardise rectum contours, unfold them into 2D cylindrical surface maps, and identify subregions where higher doses increase rectal toxicities. Materials and methods Data of 1,048 patients with prostate cancer from the REQUITE study were used. Deep learning based automatic segmentations were generated to ensure consistency. Rectum length was standardised using linear transformations superior and inferior to the prostate. The automatic contours were validated against the manual contours through contour variation assessment with cylindrical mapping. Voxel-based analysis of the dose surface maps for the manual and automatic contours against individual rectal toxicities was performed using Student's t permutation test and Cox Proportional Hazards Model (CPHM). Significance was defined by permutation testing. Results Our method enabled the analysis of 1,048 patients using automatic segmentation. Student's t-test showed significance (p < 0.05) in the lower posterior for clinical-reported proctitis and patient-reported bowel urgency. Univariable CPHM identified a 3 % increased risk per Gy for clinician-reported proctitis and a 2 % increased risk per Gy for patient-reported bowel urgency in the lower posterior. No other endpoints were significant. Conclusion We developed a methodology that unfolds the rectum to a 2D surface map. The lower posterior was significant for clinician-reported proctitis and patient-reported bowel urgency, suggesting that reducing the dose in the region could decrease toxicity risk.
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Affiliation(s)
- Artemis Bouzaki
- Division of Cancer Sciences, University of Manchester, Manchester, the United Kingdom of Great Britain and Northern Ireland
| | - Dylan Green
- Department of Engineering Science, University of Oxford, Oxford, the United Kingdom of Great Britain and Northern Ireland
| | - Marcel van Herk
- Division of Cancer Sciences, University of Manchester, Manchester, the United Kingdom of Great Britain and Northern Ireland
- The Christie NHS Foundation Trust, Manchester, the United Kingdom of Great Britain and Northern Ireland
| | - Jane Shortall
- Division of Cancer Sciences, University of Manchester, Manchester, the United Kingdom of Great Britain and Northern Ireland
- The Christie NHS Foundation Trust, Manchester, the United Kingdom of Great Britain and Northern Ireland
| | - Tanuj Puri
- Division of Cancer Sciences, University of Manchester, Manchester, the United Kingdom of Great Britain and Northern Ireland
| | - Sarah Kerns
- Medical College of Wisconsin, Milwaukee, WI, USA
| | - David Azria
- Federation Universitaire d’Oncologie Radiothérapie d’Occitanie Méditerranée, Univ Montpellier, INSERM U1194 IRCM, Institut du Cancer Montpellier (ICM), Montpellier, France
| | - Marrie-Pierre Farcy-Jacquet
- Federation Universitaire d’Oncologie Radiothérapie d’Occitanie Méditerranée, Institut du Cancer Du Gard (ICG), CHU Carémeau, Nîmes, France
| | - Jenny Chang-Claude
- German Cancer Research Center (DKFZ), Division of Cancer Epidemiology, Heidelberg, Germany
- University Cancer Center Hamburg, University Medical Center Hamburg-Eppendorf, Germany
| | - Ananya Choudhury
- Division of Cancer Sciences, University of Manchester, Manchester, the United Kingdom of Great Britain and Northern Ireland
- The Christie NHS Foundation Trust, Manchester, the United Kingdom of Great Britain and Northern Ireland
| | - Alison Dunning
- Centre for Cancer Genetic Epidemiology, Strangeways Research Laboratory, University of Cambridge, Cambridge, the United Kingdom of Great Britain and Northern Ireland
| | | | - Barbara Avuzzi
- Department of Radiation Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Dirk De Ruysscher
- Department of Radiation Oncology (Maastro), Maastricht University Medical Center, GROW School, Maastricht, the Netherlands
| | - Petra Seibold
- German Cancer Research Center (DKFZ), Division of Cancer Epidemiology, Heidelberg, Germany
| | - Elena Sperk
- Department of Radiation Oncology, Universitätsmedizin Mannheim, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany
| | - Christopher Talbot
- Department of Genetics & Cancer Sciences, University of Leicester, the United Kingdom of Great Britain and Northern Ireland
| | - Ana Vega
- Instituto de Investigación Sanitaria de Santiago de Compostela (IDIS), Santiago de Compostela, Spain
- Fundación Pública Galega de Medicina Xenómica (FPGMX), Santiago de Compostela, Spain
- Biomedical Network on Rare Diseases (CIBERER), Spain
| | - Liv Veldeman
- Ghent University Hospital, Belgium
- Ghent University, Ghent, Belgium
| | - Adam Webb
- Department of Genetics & Cancer Sciences, University of Leicester, the United Kingdom of Great Britain and Northern Ireland
| | - Barry Rosenstein
- Departments of Radiation Oncology & Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, NY, USA
| | - Catharine M. West
- Translational Radiobiology Group, Division of Cancer Sciences, University of Manchester, The Christie NHS Foundation Trust, Manchester, the United Kingdom of Great Britain and Northern Ireland
| | - Eliana Gioscio
- Data Science Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Tiziana Rancati
- Data Science Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Eliana Vasquez Osorio
- Division of Cancer Sciences, University of Manchester, Manchester, the United Kingdom of Great Britain and Northern Ireland
- The Christie NHS Foundation Trust, Manchester, the United Kingdom of Great Britain and Northern Ireland
| | - Alan McWilliam
- Division of Cancer Sciences, University of Manchester, Manchester, the United Kingdom of Great Britain and Northern Ireland
- The Christie NHS Foundation Trust, Manchester, the United Kingdom of Great Britain and Northern Ireland
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Lindgren A, Börjeson S, Dunberger G. Female pelvic cancer survivors' experiences of pelvic floor muscle training after pelvic radiotherapy. Support Care Cancer 2024; 32:844. [PMID: 39623242 PMCID: PMC11611980 DOI: 10.1007/s00520-024-09041-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2024] [Accepted: 11/20/2024] [Indexed: 12/06/2024]
Abstract
PURPOSE To describe experiences of a 3-month pelvic floor muscle training (PFMT) period, with or without support from a physiotherapist, among females with urinary and/or fecal incontinence after pelvic radiotherapy. METHOD This qualitative interview study included eleven women (aged 47-83 years) with urinary and/or fecal incontinence after radiotherapy treatment for pelvic cancer (radiotherapy completed 3-60 months ago). The eleven informants were part of a larger randomized controlled intervention study where they practiced PFMT, with or without support from a physiotherapist, for 3 months. The support from a physiotherapist included individual support with biofeedback as well as group training. The women were interviewed individually soon after the completion of the pelvic floor muscle training period, and data were analyzed with qualitative content analysis. RESULT A structured training program, individual support from a physiotherapist, and strategies to establish a daily workout routine were described as valuable when practicing pelvic floor muscle training. Participating in the study gave a sense of meaningfulness and motivation to practice, partly due to the knowledge of a follow-up after the study period. Group and home training were described as both a facilitator and a barrier to PFMT. The women experienced that PFMT had influenced pelvic floor function in terms of increased pelvic floor strength, reduced urinary and fecal incontinence, and an increased ability to hold urine and feces during urgency. PFMT had a relieving effect on pelvic floor pain, although it also contributed to some increase in pain. The perceived improvement in pelvic muscle function led to decreased anxiety, increased safety, feelings of greater freedom in everyday life, a changed attitude toward physical activity, and improved sexual health. All women expressed an intention to continue practicing PFMT and a desire for information and opportunities for PFMT, under the guidance of a physiotherapist, to be implemented in conventional pelvic cancer rehabilitation and made available to all women after pelvic cancer treatment. CONCLUSION The women who live with the experience of pelvic cancer experienced PFMT as a meaningful intervention for managing urinary and/or fecal incontinence after pelvic radiotherapy. They considered that information and support from a physiotherapist are essential in pelvic cancer rehabilitation, such as PFMT, and should be offered to all women after pelvic cancer treatment.
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Affiliation(s)
- A Lindgren
- Department of Health, Medicine, and Caring Sciences, Division of Prevention, Rehabilitation and Community Medicine, Linköping University, 58183, Linköping, Sweden.
| | - S Börjeson
- Department of Health, Medicine, and Caring Sciences, Division of Caring Sciences and Reproductive Health, Linköping University, Linköping, Sweden
| | - G Dunberger
- Department of Health Care Sciences, Marie Cederschiöld University, Stockholm, Sweden
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Feakins RM. Inflammatory disorders of the large intestine. MORSON AND DAWSON'S GASTROINTESTINAL PATHOLOGY 2024:709-857. [DOI: 10.1002/9781119423195.ch35] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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Berntsson H, Thien A, Hind D, Stewart L, Mahzabin M, Tung WS, Bradburn M, Kurien M. Interventions for Managing Late Gastrointestinal Symptoms Following Pelvic Radiotherapy: a Systematic Review and Meta-analysis. Clin Oncol (R Coll Radiol) 2024; 36:318-334. [PMID: 38431427 DOI: 10.1016/j.clon.2024.02.011] [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: 09/29/2023] [Revised: 01/04/2024] [Accepted: 02/15/2024] [Indexed: 03/05/2024]
Abstract
AIMS Pelvic radiotherapy can induce gastrointestinal injury and symptoms, which can affect quality of life. We assessed interventions for managing these symptoms. MATERIALS AND METHODS A review of randomised controlled trials published between January 1990 and June 2023 from databases including MEDLINE, EMBASE, CENTRAL, CINAHL, clinicaltrials.gov, ISRCTN and grey literature sources was conducted. Meta-analyses were carried out using the DerSimonian and Laird random effects model to produce overall treatment differences with 95% confidence intervals. RESULTS Twenty-eight studies (2392 participants) of varying methodological quality were included. 4% formalin was superior to sucralfate for improving gastrointestinal symptom score (standardised mean difference [SMD] -1.07, 95% confidence interval -1.48 to -0.65). Argon plasma coagulation (APC) was inferior to sucralfate (SMD 1.22, 95% confidence interval 0.84 to 1.59). Counselling positively influenced symptom score (SMD -0.53, 95% confidence interval -0.76 to -0.29), whereas hyperbaric oxygen therapy showed conflicting results. Sucralfate combined with APC increased endoscopic markers of moderate-severe bleeding versus APC alone (risk ratio 2.26, 95% confidence interval 1.12 to 4.55). No definite conclusions on pain, incontinence, diarrhoea, tenesmus or quality of life interventions were confirmed. CONCLUSIONS Small study sizes, methodological quality and heterogeneity limit support of any individual intervention. APC and 4% formalin seem to be promising interventions, with further larger randomised controlled trials now warranted.
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Affiliation(s)
- H Berntsson
- Sheffield Centre for Health and Related Research, University of Sheffield, Sheffield, UK.
| | - A Thien
- Department of General Surgery, Raja Isteri Pengiran Anak Saleha Hospital, Bandar Seri Begawan, Brunei
| | - D Hind
- Sheffield Centre for Health and Related Research, University of Sheffield, Sheffield, UK
| | - L Stewart
- The Medical School, University of Sheffield, Sheffield, UK
| | - M Mahzabin
- The Medical School, University of Sheffield, Sheffield, UK
| | - W S Tung
- The Medical School, University of Sheffield, Sheffield, UK
| | - M Bradburn
- Sheffield Centre for Health and Related Research, University of Sheffield, Sheffield, UK
| | - M Kurien
- The Medical School, University of Sheffield, Sheffield, UK
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Fijardo M, Kwan JYY, Bissey PA, Citrin DE, Yip KW, Liu FF. The clinical manifestations and molecular pathogenesis of radiation fibrosis. EBioMedicine 2024; 103:105089. [PMID: 38579363 PMCID: PMC11002813 DOI: 10.1016/j.ebiom.2024.105089] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2024] [Revised: 02/25/2024] [Accepted: 03/12/2024] [Indexed: 04/07/2024] Open
Abstract
Advances in radiation techniques have enabled the precise delivery of higher doses of radiotherapy to tumours, while sparing surrounding healthy tissues. Consequently, the incidence of radiation toxicities has declined, and will likely continue to improve as radiotherapy further evolves. Nonetheless, ionizing radiation elicits tissue-specific toxicities that gradually develop into radiation-induced fibrosis, a common long-term side-effect of radiotherapy. Radiation fibrosis is characterized by an aberrant wound repair process, which promotes the deposition of extensive scar tissue, clinically manifesting as a loss of elasticity, tissue thickening, and organ-specific functional consequences. In addition to improving the existing technologies and guidelines directing the administration of radiotherapy, understanding the pathogenesis underlying radiation fibrosis is essential for the success of cancer treatments. This review integrates the principles for radiotherapy dosimetry to minimize off-target effects, the tissue-specific clinical manifestations, the key cellular and molecular drivers of radiation fibrosis, and emerging therapeutic opportunities for both prevention and treatment.
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Affiliation(s)
- Mackenzie Fijardo
- Research Institute, Princess Margaret Cancer Centre, Toronto, Ontario, Canada; Department of Cell and Systems Biology, University of Toronto, Toronto, Ontario, Canada
| | - Jennifer Yin Yee Kwan
- Research Institute, Princess Margaret Cancer Centre, Toronto, Ontario, Canada; Radiation Medicine Program, Princess Margaret Cancer Centre, Toronto, Ontario, Canada; Department of Radiation Oncology, University of Toronto, Toronto, Ontario, Canada; Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada
| | | | - Deborah E Citrin
- Radiation Oncology Branch, National Cancer Institute, Bethesda, MD, United States of America
| | - Kenneth W Yip
- Research Institute, Princess Margaret Cancer Centre, Toronto, Ontario, Canada; Department of Cell and Systems Biology, University of Toronto, Toronto, Ontario, Canada
| | - Fei-Fei Liu
- Research Institute, Princess Margaret Cancer Centre, Toronto, Ontario, Canada; Radiation Medicine Program, Princess Margaret Cancer Centre, Toronto, Ontario, Canada; Department of Radiation Oncology, University of Toronto, Toronto, Ontario, Canada; Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada; Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.
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Wu L, Chen L, Li H, Wang Y, Xu K, Chen W, Zhang A, Wang Y, Shi C. Nocardia rubra cell-wall skeleton mitigates whole abdominal irradiation-induced intestinal injury via regulating macrophage function. BURNS & TRAUMA 2024; 12:tkad045. [PMID: 38444637 PMCID: PMC10914217 DOI: 10.1093/burnst/tkad045] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 12/13/2022] [Revised: 04/13/2023] [Accepted: 08/16/2023] [Indexed: 03/07/2024]
Abstract
Background Ionizing radiation (IR)-induced intestinal injury is a major side effect and dose-limiting toxicity in patients receiving radiotherapy. There is an urgent need to identify an effective and safe radioprotectant to reduce radiation-induced intestinal injury. Immunoregulation is considered an effective strategy against IR-induced injury. The purpose of this article was to investigate the protective effect of Nocardia rubra cell wall skeleton (Nr-CWS), an immunomodulator, on radiation-induced intestinal damage and to explore its potential mechanism. Methods C57BL/6 J male mice exposed to 12 Gy whole abdominal irradiation (WAI) were examined for survival rate, morphology and function of the intestine and spleen, as well as the gut microbiota, to comprehensively evaluate the therapeutic effects of Nr-CWS on radiation-induced intestinal and splenetic injury. To further elucidate the underlying mechanisms of Nr-CWS-mediated intestinal protection, macrophages were depleted by clodronate liposomes to determine whether Nr-CWS-induced radioprotection is macrophage dependent, and the function of peritoneal macrophages stimulated by Nr-CWS was detected in vitro. Results Our data showed that Nr-CWS promoted the recovery of intestinal barrier function, enhanced leucine-rich repeat-containing G protein-coupled receptor 5+ intestinal stem cell survival and the regeneration of intestinal epithelial cells, maintained intestinal flora homeostasis, protected spleen morphology and function, and improved the outcome of mice exposed to 12 Gy WAI. Mechanistic studies indicated that Nr-CWS recruited macrophages to reduce WAI-induced intestinal damage. Moreover, macrophage depletion by clodronate liposomes blocked Nr-CWS-induced radioprotection. In vitro, we found that Nr-CWS activated the nuclear factor kappa-B signaling pathway and promoted the phagocytosis and migration ability of peritoneal macrophages. Conclusions Our study suggests the therapeutic effect of Nr-CWS on radiation-induced intestinal injury, and provides possible therapeutic strategy and potential preventive and therapeutic drugs to alleviate it.
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Affiliation(s)
- Lingling Wu
- Department of Toxicology, School of Public Health, Guizhou Medical University, Guiyang, 550025, China
- State Key Laboratory of Trauma and Chemical Poisoning, Third Military Medical University (Army Medical University), 400038, Chongqing, China
| | - Long Chen
- State Key Laboratory of Trauma and Chemical Poisoning, Third Military Medical University (Army Medical University), 400038, Chongqing, China
| | - Huijuan Li
- State Key Laboratory of Trauma and Chemical Poisoning, Third Military Medical University (Army Medical University), 400038, Chongqing, China
| | - Yawei Wang
- State Key Laboratory of Trauma and Chemical Poisoning, Third Military Medical University (Army Medical University), 400038, Chongqing, China
| | - Kexin Xu
- State Key Laboratory of Trauma and Chemical Poisoning, Third Military Medical University (Army Medical University), 400038, Chongqing, China
- College of Biological Engineering, Chongqing University 400044, Chongqing, China
| | - Wanchao Chen
- State Key Laboratory of Trauma and Chemical Poisoning, Third Military Medical University (Army Medical University), 400038, Chongqing, China
| | - Aihua Zhang
- Department of Toxicology, School of Public Health, Guizhou Medical University, Guiyang, 550025, China
| | - Yu Wang
- State Key Laboratory of Trauma and Chemical Poisoning, Third Military Medical University (Army Medical University), 400038, Chongqing, China
| | - Chunmeng Shi
- Department of Toxicology, School of Public Health, Guizhou Medical University, Guiyang, 550025, China
- State Key Laboratory of Trauma and Chemical Poisoning, Third Military Medical University (Army Medical University), 400038, Chongqing, China
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Wright JP, Guerrero WM, Lucking JR, Bustamante-Lopez L, Monson JRT. The double-barrel wet colostomy: An alternative for urinary diversion after pelvic exenteration. Surgeon 2023; 21:375-380. [PMID: 37087331 DOI: 10.1016/j.surge.2023.03.004] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2022] [Revised: 03/15/2023] [Accepted: 03/21/2023] [Indexed: 04/24/2023]
Abstract
AIM Pelvic exenteration is a radical procedure used to treat locally advanced and/or recurrent pelvic malignancies. Different reconstruction options exist, the most popular being the end colostomy with ileal conduit. The double barrel wet colostomy (DBWC) offers concomitant fecal and urinary diversion through a single stoma, but is infrequently utilized. We aim to review the evidence base of the postoperative complications, long-term oncologic risks and quality of life following creation of a double barrel wet colostomy. METHODS A narrative review of the literature was performed evaluating the DBWC. Patient demographics, perioperative complications, operative variables, long terms oncologic outcomes and quality of life data were extracted. Descriptive statistics were used to define the data. RESULTS Fourteen articles with a total of 300 patients undergoing DBWC following pelvic exenteration were selected. 41% of malignancies were gastrointestinal in origin while 41.7% were gynecologic and 5.3% genitourinary. 42% of patients experienced at least one complication within in 40 days of surgery, the most common being wound infection (8.7%) and urinary leak (8.3%). There was no evidence of malignancy within the DBWC during long-term surveillance. Quality of life following DBWC is comparable to other reconstructive methods. CONCLUSION The DBWC is a well described reconstructive method for urinary and fecal diversion utilizing a single stoma following pelvic exenteration. The short- and long-term outcomes following DBWC are comparable to other reconstructive methods and the quality of life with a DBWC is acceptable. DBWC should remain a readily available option for reconstruction following pelvic exenteration.
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Affiliation(s)
- Jesse P Wright
- Baptist Memorial Hospital, Oncology Surgical Services, Memphis, TN, USA.
| | | | | | - Leonardo Bustamante-Lopez
- AdventHealth Medical Group Colorectal Surgery, AdventHealth-Orlando, Surgical Health Outcomes Consortium, Orlando, FL, USA.
| | - John R T Monson
- AdventHealth Medical Group Colorectal Surgery, AdventHealth-Orlando, Surgical Health Outcomes Consortium, Orlando, FL, USA.
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Yan Z, Yin B, Wang Y, Ni Z, Feng J, Yang Q, Li X, Zhu H, Dou Y. Therapeutic mechanism of Liangxue-Guyuan-Yishen decoction on intestinal stem cells and tight junction proteins in gastrointestinal acute radiation syndrome rats. JOURNAL OF RADIATION RESEARCH 2023; 64:880-892. [PMID: 37697698 PMCID: PMC10665307 DOI: 10.1093/jrr/rrad065] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/23/2023] [Revised: 05/04/2023] [Accepted: 08/19/2023] [Indexed: 09/13/2023]
Abstract
On the basis of the previous research, the Traditional Chinese Medicine theory was used to improve the drug composition for gastrointestinal acute radiation syndrome (GI-ARS). The purpose of this study was to study the therapeutic mechanism of Liangxue-Guyuan-Yishen decoction (LGYD) on GI-ARS and to provide a new scheme for the treatment of radiation injury. Here, we investigated the effects of LGYD on intestinal stem cells (ISCs) in a GI-ARS rat model. Rat health and survival and the protective efficacy of LGYD on the intestines were analyzed. The active principles in LGYD were detected using liquid chromatography-mass spectrometry (LC-MS). ISC proliferation, intestinal epithelial tight junction (TJ) protein expression and regulatory pathways were explored using immunohistochemistry, western blotting (WB) and reverse transcription quantitative polymerase chain reaction (RT-qPCR), respectively. Involvement of the WNT and MEK/ERK pathways in intestinal recovery was screened using network pharmacology analysis and validated by WB and RT-qPCR. LGYD administration significantly improved health and survival in GI-ARS rats. Pathological analysis showed that LGYD ameliorated radiation-induced intestinal injury and significantly promoted LGR5+ stem cell regeneration in the intestinal crypts, upregulated TJ protein, and accelerated crypt reconstruction in the irradiated rats. LC-MS revealed ≥13 constituents that might contribute to LGYD's protective effects. Collectively, LGYD can promote crypt cell proliferation and ISCs after radiation damage, the above effect may be related to WNT and MEK/ERK pathway.
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Affiliation(s)
- Ziqiao Yan
- Department of Traditional Chinese Medicine, The First Medical Center of Chinese People’s Liberation Army (PLA) General Hospital, Fuxing Road 28th, Haidian District, Beijing, 10038, China
- Chinese PLA Medical School, Chinese People’s Liberation Army (PLA) General Hospital, Fuxing Road 28th, Haidian District, Beijing, 10038, China
| | - Bofeng Yin
- Department of Experimental Hematology and Biochemistry, Beijing Institute of Radiation Medicine, Taiping Road 27th, Haidian District, Beijing, 10039, China
- Beijing Key Laboratory for Radiobiology, Beijing Institute of Radiation Medicine, Taiping Road 27th, Haidian District, Beijing, 10039, China
| | - Yuguo Wang
- Department of Traditional Chinese Medicine, The Sixth Medical Center of Chinese People’s Liberation Army (PLA) General Hospital, Fucheng Road 6th, Haidian District, Beijing, 10037, China
| | - Zhexin Ni
- Department of Pharmaceutical Sciences, Beijing Institute of Radiation Medicine, Taiping Road 27th, Haidian District, Beijing, 10039, China
| | - Jian Feng
- Department of Traditional Chinese Medicine, The Chinese People’s Liberation Army (PLA) 96604 Hospital, Jingningnan Road 72th, Chengguan District, Lanzhou, 730030, China
| | - Qianyu Yang
- Graduate School of Hebei University of Chinese Medicine, Xinshinan Road 326th, Qiaoxi District, Shijiazhuang, Hebei, 050090, China
| | - Xiao Li
- Chinese PLA Medical School, Chinese People’s Liberation Army (PLA) General Hospital, Fuxing Road 28th, Haidian District, Beijing, 10038, China
| | - Heng Zhu
- Department of Experimental Hematology and Biochemistry, Beijing Institute of Radiation Medicine, Taiping Road 27th, Haidian District, Beijing, 10039, China
- Beijing Key Laboratory for Radiobiology, Beijing Institute of Radiation Medicine, Taiping Road 27th, Haidian District, Beijing, 10039, China
- Beijing Institute of Basic Medical Sciences, Taiping Road 27th, Haidian District, Beijing, 10039, China
- Graduate School of Anhui Medical University, Meishan Road 69th, Shushan District, Hefei, Anhui, 230022, China
| | - Yongqi Dou
- Department of Traditional Chinese Medicine, The First Medical Center of Chinese People’s Liberation Army (PLA) General Hospital, Fuxing Road 28th, Haidian District, Beijing, 10038, China
- Chinese PLA Medical School, Chinese People’s Liberation Army (PLA) General Hospital, Fuxing Road 28th, Haidian District, Beijing, 10038, China
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Chen Q, Yao L, Liu Q, Hou J, Qiu X, Chen M, Wu Z, Hu D, Cui F, Yan T. Exosome-coated polydatin nanoparticles in the treatment of radiation-induced intestinal damage. Aging (Albany NY) 2023; 15:6905-6920. [PMID: 37466428 PMCID: PMC10415572 DOI: 10.18632/aging.204882] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2023] [Accepted: 06/22/2023] [Indexed: 07/20/2023]
Abstract
This study aimed to develop an exosome-coated polydatin (PD) nanoparticles (exo-PD) for improving the water solubility and bioavailability of polydatin and explore its salutary effects on intestinal radiation injury. Exosomes (exo) were extracted from the medium of human amniotic fluid stem cells (hAFSc). Mice were divided into control group, irradiation (IR) group, irradiation+PD (IR+PD) group, irradiation+exo (IR+exo) group and irradiation+exo-PD (IR+exo-PD) group. The results of characterization of protein markers, particle size, morphology and cellular uptake ability confirmed that exosomes were effectively isolated using ultracentrifugation. Compared with the IR group, exo-PD improved cell viability, prolonged survival of mice, improved leukocyte count and reduced diarrhea rate. Histological results showed that the exo-PD group had significant improvements in small intestinal villus length and crypt number and less crypt cell damage. exo-PD could reduce IL-1α and IL-6 levels, reduced γ-H2AX expression, increased mitochondrial membrane potential, enhanced oxidative phosphorylation, and delayed cellular senescence. exo-PD could alleviate intestinal injury by improving mitochondrial function through PI3K-AKT pathway. The exo-PD was able to reduce radiation damage to intestinal cells and could be a potential candidate for salvage of intestinal radiation damage.
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Affiliation(s)
- Qiu Chen
- State Key Laboratory of Radiation Medicine and Protection, School of Radiation Medicine and Protection, Soochow University, Suzhou 215123, China
- Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education Institutions, Suzhou 215123, China
| | - Lei Yao
- State Key Laboratory of Radiation Medicine and Protection, School of Radiation Medicine and Protection, Soochow University, Suzhou 215123, China
- Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education Institutions, Suzhou 215123, China
| | - Quanbin Liu
- Rocket Force Specialty Medical Center PLA, Beijing 100088, China
| | - Jun Hou
- Department of Pathology, Zhongshan Hospital, Fudan University, Shanghai 200032, China
| | - Xinyu Qiu
- State Key Laboratory of Radiation Medicine and Protection, School of Radiation Medicine and Protection, Soochow University, Suzhou 215123, China
- Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education Institutions, Suzhou 215123, China
| | - Mengyuan Chen
- State Key Laboratory of Radiation Medicine and Protection, School of Radiation Medicine and Protection, Soochow University, Suzhou 215123, China
- Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education Institutions, Suzhou 215123, China
| | - Zhuojun Wu
- State Key Laboratory of Radiation Medicine and Protection, School of Radiation Medicine and Protection, Soochow University, Suzhou 215123, China
- Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education Institutions, Suzhou 215123, China
| | - Duanmin Hu
- Department of Gastroenterology, The Second Affiliated Hospital of Soochow University, Suzhou 215123, China
| | - Fengmei Cui
- State Key Laboratory of Radiation Medicine and Protection, School of Radiation Medicine and Protection, Soochow University, Suzhou 215123, China
- Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education Institutions, Suzhou 215123, China
| | - Tao Yan
- Rocket Force Specialty Medical Center PLA, Beijing 100088, China
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Kenchegowda D, Bolduc DL, Kurada L, Blakely WF. Severity scoring systems for radiation-induced GI injury - Prioritization for use of GI-ARS medical countermeasures. Int J Radiat Biol 2023:1-9. [PMID: 37172305 DOI: 10.1080/09553002.2023.2210669] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/14/2023]
Abstract
PURPOSE Severity scoring systems for ionizing radiation-induced gastrointestinal injury have been used in animal radiation models, human studies involving the use of radiation therapy, and radiation accidents. Various radiation exposure scenarios (i.e., total body irradiation, total abdominal irradiation, etc.) have been used to investigate ionizing radiation-induced gastrointestinal injury. These radiation-induced GI severity scoring systems are based on clinical signs and symptoms and gastrointestinal-specific biomarkers (i.e., citrulline, etc.). In addition, the time course for radiation-induced changes in blood citrulline levels were compared across various animal (i.e., mice, minipigs, Rhesus Macaque, etc.) and human model systems. CONCLUSIONS A worksheet tool was developed to prioritize individuals with severe life-threatening gastrointestinal acute radiation syndrome, based on the design of the Exposure and Symptom Tool addressing hematopoietic acute radiation syndrome, to rescue individuals from potential gastrointestinal acute radiation syndrome injury. This tool provides a triage diagnostic approach to assist first-responders to assess individuals suspected of showing gastrointestinal acute radiation syndrome severity to guide medical management, hence enhancing medical readiness for managing radiological casualties.
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Affiliation(s)
- Doreswamy Kenchegowda
- Biodosimetry Program, Scientific Research Department, Armed Forces Radiobiology Research Institute, Uniformed Services University of the Health Sciences, Bethesda, MD, USA
| | - David L Bolduc
- Biodosimetry Program, Scientific Research Department, Armed Forces Radiobiology Research Institute, Uniformed Services University of the Health Sciences, Bethesda, MD, USA
| | - Lalitha Kurada
- Biodosimetry Program, Scientific Research Department, Armed Forces Radiobiology Research Institute, Uniformed Services University of the Health Sciences, Bethesda, MD, USA
- Henry M Jackson Foundation, 6720A Rockledge Drive, Bethesda, MD USA
| | - William F Blakely
- Biodosimetry Program, Scientific Research Department, Armed Forces Radiobiology Research Institute, Uniformed Services University of the Health Sciences, Bethesda, MD, USA
- Department of Preventive Medicine and Biostatistics, Uniformed Services University of the Health Sciences, Bethesda, MD, USA
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11
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Fernandes A, Oliveira A, Soares R, Barata P. The Effects of Ionizing Radiation on Gut Microbiota: What Can Animal Models Tell Us?-A Systematic Review. Curr Issues Mol Biol 2023; 45:3877-3910. [PMID: 37232718 DOI: 10.3390/cimb45050249] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2023] [Revised: 04/16/2023] [Accepted: 04/27/2023] [Indexed: 05/27/2023] Open
Abstract
BACKGROUND The gut microbiota is relatively stable; however, various factors can precipitate an imbalance that is known to be associated with various diseases. We aimed to conduct a systematic literature review of studies reporting the effects of ionizing radiation on the composition, richness, and diversity of the gut microbiota of animals. METHODS A systematic literature search was performed in PubMed, EMBASE, and Cochrane library databases. The standard methodologies expected by Cochrane were utilized. RESULTS We identified 3531 non-duplicated records and selected twenty-nine studies after considering the defined inclusion criteria. The studies were found to be heterogeneous, with significant differences in the chosen populations, methodologies, and outcomes. Overall, we found evidence of an association between ionizing radiation exposure and dysbiosis, with a reduction of microbiota diversity and richness and alterations in the taxonomic composition. Although differences in taxonomic composition varied across studies, Proteobacteria, Verrucomicrobia, Alistipes, and Akkermancia most consistently reported to be relatively more abundant after ionizing radiation exposure, whereas Bacteroidetes, Firmicutes, and Lactobacillus were relatively reduced. CONCLUSIONS This review highlights the effect of ionizing exposure on gut microbiota diversity, richness, and composition. It paves the way for further studies on human subjects regarding gastrointestinal side effects in patients submitted to treatments with ionizing radiation and the development of potential preventive, therapeutic approaches.
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Affiliation(s)
- Ana Fernandes
- Department Nuclear Medicine, Centro Hospitalar e Universitário de São João, E.P.E., 4200-319 Porto, Portugal
| | - Ana Oliveira
- Department Nuclear Medicine, Centro Hospitalar e Universitário de São João, E.P.E., 4200-319 Porto, Portugal
| | - Raquel Soares
- i3S-Institute for Research and Innovation in Health, Universidade do Porto, 4200-135 Porto, Portugal
- Department of Biomedicine, Faculdade de Medicina, Universidade do Porto, 4200-319 Porto, Portugal
| | - Pedro Barata
- i3S-Institute for Research and Innovation in Health, Universidade do Porto, 4200-135 Porto, Portugal
- Faculdade de Ciências da Saúde, Universidade Fernando Pessoa, 4200-150 Porto, Portugal
- Department of Pathology, Centro Hospitalar Universitário do Porto, 4099-001 Porto, Portugal
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12
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Klett KC, Martin-Villa BC, Villarreal VS, Melemenidis S, Viswanathan V, Manjappa R, Ashraf MR, Soto L, Lau B, Dutt S, Rankin EB, Loo BW, Heilshorn SC. Human enteroids as a tool to study conventional and ultra-high dose rate radiation. Integr Biol (Camb) 2023; 15:zyad013. [PMID: 37874173 PMCID: PMC10594601 DOI: 10.1093/intbio/zyad013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2023] [Revised: 09/22/2023] [Accepted: 09/26/2023] [Indexed: 10/25/2023]
Abstract
Radiation therapy, one of the most effective therapies to treat cancer, is highly toxic to healthy tissue. The delivery of radiation at ultra-high dose rates, FLASH radiation therapy (FLASH), has been shown to maintain therapeutic anti-tumor efficacy while sparing normal tissues compared to conventional dose rate irradiation (CONV). Though promising, these studies have been limited mainly to murine models. Here, we leveraged enteroids, three-dimensional cell clusters that mimic the intestine, to study human-specific tissue response to radiation. We observed enteroids have a greater colony growth potential following FLASH compared with CONV. In addition, the enteroids that reformed following FLASH more frequently exhibited proper intestinal polarity. While we did not observe differences in enteroid damage across groups, we did see distinct transcriptomic changes. Specifically, the FLASH enteroids upregulated the expression of genes associated with the WNT-family, cell-cell adhesion, and hypoxia response. These studies validate human enteroids as a model to investigate FLASH and provide further evidence supporting clinical study of this therapy. Insight Box Promising work has been done to demonstrate the potential of ultra-high dose rate radiation (FLASH) to ablate cancerous tissue, while preserving healthy tissue. While encouraging, these findings have been primarily observed using pre-clinical murine and traditional two-dimensional cell culture. This study validates the use of human enteroids as a tool to investigate human-specific tissue response to FLASH. Specifically, the work described demonstrates the ability of enteroids to recapitulate previous in vivo findings, while also providing a lens through which to probe cellular and molecular-level responses to FLASH. The human enteroids described herein offer a powerful model that can be used to probe the underlying mechanisms of FLASH in future studies.
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Affiliation(s)
- Katarina C Klett
- Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA, USA
| | | | - Victoria S Villarreal
- Department of Materials Science and Engineering, Stanford University, Stanford, CA, USA
| | - Stavros Melemenidis
- Department of Radiation Oncology, Stanford University School of Medicine, Stanford, CA, USA
| | - Vignesh Viswanathan
- Department of Radiation Oncology, Stanford University School of Medicine, Stanford, CA, USA
| | - Rakesh Manjappa
- Department of Radiation Oncology, Stanford University School of Medicine, Stanford, CA, USA
| | - M Ramish Ashraf
- Department of Radiation Oncology, Stanford University School of Medicine, Stanford, CA, USA
| | - Luis Soto
- Department of Radiation Oncology, Stanford University School of Medicine, Stanford, CA, USA
| | - Brianna Lau
- Department of Radiation Oncology, Stanford University School of Medicine, Stanford, CA, USA
| | - Suparna Dutt
- Department of Radiation Oncology, Stanford University School of Medicine, Stanford, CA, USA
| | - Erinn B Rankin
- Department of Radiation Oncology, Stanford University School of Medicine, Stanford, CA, USA
- Department of Obstetrics and Gynecology, Stanford University School of Medicine, Stanford, CA, USA
- Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA
| | - Billy W Loo
- Department of Radiation Oncology, Stanford University School of Medicine, Stanford, CA, USA
- Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA
| | - Sarah C Heilshorn
- Department of Materials Science and Engineering, Stanford University, Stanford, CA, USA
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13
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Amit U, Facciabene A, Ben-Josef E. Radiation Therapy and the Microbiome; More Than a Gut Feeling. Cancer J 2023; 29:84-88. [PMID: 36957978 DOI: 10.1097/ppo.0000000000000650] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/25/2023]
Abstract
ABSTRACT It is increasingly recognized that heterogeneities in tumor response and severity of adverse effects in irradiated patients can be attributed to the tumor microenvironment and host-related factors. Among the latter, a growing body of literature in recent years has demonstrated the role of the patient's microbiome in modulating both tumor and normal tissue response to radiotherapy (RT). Upon contact with the environment after birth, the infant's gastrointestinal tract is rapidly colonized by microbiota, which is low in diversity and predominantly characterized by 2 dominant species, Actinobacteria and Proteobacteria. With time, intestinal microbiota diversity increases, and colonization of Firmicutes and Bacteroidetes becomes dominant. By the time a child reaches 3 years, the gut microbiota composition has been reshaped and is relatively similar to that of an adult. The microbiome colonizing the different body organs comprises various species and abundances, which may impact human health. Although the adult microbiome composition is thought to remain stable in health, microbiome diversity and composition respond to different environmental and pathological conditions, including pharmaceutical interventions and RT. Our review focuses on how the gut microbiota modulates normal tissue toxicity and tumor control. Readers who want to learn more about how RT shapes gut microbiome diversity and composition are referred to several excellent recently published reviews.
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Affiliation(s)
| | | | - Edgar Ben-Josef
- From the Department of Radiation Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA
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14
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Duan X, Cai H, Hu T, Lin L, Zeng L, Wang H, Cao L, Li X. Ginsenoside Rg3 treats acute radiation proctitis through the TLR4/MyD88/NF-κB pathway and regulation of intestinal flora. Front Cell Infect Microbiol 2023; 12:1028576. [PMID: 36683687 PMCID: PMC9853003 DOI: 10.3389/fcimb.2022.1028576] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2022] [Accepted: 12/12/2022] [Indexed: 01/07/2023] Open
Abstract
Objectives This study aimed to investigate the protective effect of ginsenoside Rg3 (GRg3) against acute radiation proctitis (ARP) in rats. Methods Wistar rats were randomly divided into control, model, dexamethasone-positive, GRg3 low-dose, GRg3 medium-dose, and GRg3 high-dose groups. The ARP rat model was established by a single 22-Gy irradiation of 6 MV) X-rays. The distribution and function of intestinal flora were detected using 16S rRNA high-throughput sequencing, rectal tissue was observed by hematoxylin and eosin (H&E) staining, the expression of interleukin 1β (IL-1β) and IL-10 inflammatory factors was detected by ELISA, and mRNA and protein expression of toll-like receptor 4 (TLR4), myeloid differentiation primary response 88 (MyD88), and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) were detected by RT-qPCR and Western blotting, respectively. Results GRg3 improved the symptoms of ARP in rats in a dose-dependent manner. The species distribution of intestinal flora in GRg3 rats was significantly different from that in ARP rats. These differences were more significant in the high-dose group, where the numbers of Ruminococcus, Lactobacillus, and other beneficial bacteria were significantly increased, whereas those of Escherichia, Alloprevotella, and other harmful bacteria were decreased. In addition, GRg3 was closely related to amino acid metabolism. After GRg3 treatment, the mRNA and protein expression of TLR4, MyD88, and NF-κB in rectal tissue was significantly down-regulated, and the level of downstream inflammatory factor IL-1β decreased, whereas that of IL-10 increased. Conclusion Our study indicated GRg3 as a new compound for the treatment of ARP by inhibiting the TLR4/MyD88/NF-κB pathway, down-regulating the expression of proinflammatory factors, thus effectively regulating intestinal flora and reducing inflammatory reactions.
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Affiliation(s)
- Xiaoyu Duan
- The First Clinical Medical College of Gansu University of Chinese Medicine (Gansu Provincial Hospital), Lanzhou, China
| | - Hongyi Cai
- Department of Radiotherapy, Gansu Provincial Hospital, Lanzhou, China
| | - Tingting Hu
- Department of Radiotherapy, Gansu Provincial Hospital, Lanzhou, China
| | - Lili Lin
- The First Clinical Medical College of Gansu University of Chinese Medicine (Gansu Provincial Hospital), Lanzhou, China
| | - Lu Zeng
- The First Clinical Medical College of Gansu University of Chinese Medicine (Gansu Provincial Hospital), Lanzhou, China
| | - Huixia Wang
- The First Clinical Medical College of Gansu University of Chinese Medicine (Gansu Provincial Hospital), Lanzhou, China
| | - Lei Cao
- The First Clinical Medical College of Gansu University of Chinese Medicine (Gansu Provincial Hospital), Lanzhou, China
| | - Xuxia Li
- The First Clinical Medical College of Gansu University of Chinese Medicine (Gansu Provincial Hospital), Lanzhou, China
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15
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Abstract
The benefit of radiation is immense in the field of gastroenterology. Radiation is used daily in different gastrointestinal imaging and diagnostic and therapeutic interventional procedures. Radiotherapy is one of the primary modalities of treatment of gastrointestinal malignancies. There are various modalities of radiotherapy. Radiotherapy can injure malignant cells by directly damaging DNA, RNA, proteins, and lipids and indirectly by forming free radicals. External beam radiation, internal beam radiation and radio-isotope therapy are the major ways of delivering radiation to the malignant tissue. Radiation can also cause inflammation, fibrosis, organ dysfunction, and malignancy. Patients with repeated exposure to radiation for diagnostic imaging and therapeutic procedures are at slightly increased risk of malignancy. Gastrointestinal endoscopists performing fluoroscopy-guided procedures are also at increased risk of malignancy and cataract formation. The radiological protection society recommends certain preventive and protective measures to avoid side effects of radiation. Gastrointestinal complications related to radiation therapy for oncologic processes, and exposure risks for patients and health care providers involved in diagnostic or therapeutic imaging will be discussed in this review.
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Affiliation(s)
- Monjur Ahmed
- Division of Gastroenterology and Hepatology, Thomas Jefferson University, Philadelphia, PA 19107, USA
| | - Razin Ahmed
- California Cancer Associates for Research and Excellence, Fresno, CA, USA
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16
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Larrey EK, Pathak R. Radiation-Induced Intestinal Normal Tissue Toxicity: Implications for Altered Proteome Profile. Genes (Basel) 2022; 13:2006. [PMID: 36360243 PMCID: PMC9689954 DOI: 10.3390/genes13112006] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2022] [Revised: 10/10/2022] [Accepted: 10/31/2022] [Indexed: 09/12/2023] Open
Abstract
Radiation-induced toxicity to healthy/normal intestinal tissues, especially during radiotherapy, limits the radiation dose necessary to effectively eradicate tumors of the abdomen and pelvis. Although the pathogenesis of intestinal radiation toxicity is highly complex, understanding post-irradiation alterations in protein profiles can provide crucial insights that make radiotherapy safer and more efficient and allow for increasing the radiation dose during cancer treatment. Recent preclinical and clinical studies have advanced our current understanding of the molecular changes associated with radiation-induced intestinal damage by assessing changes in protein expression with mass spectrometry-based approaches and 2-dimensional difference gel electrophoresis. Studies by various groups have demonstrated that proteins that are involved in the inflammatory response, the apoptotic pathway, reactive oxygen species scavenging, and cell proliferation can be targeted to develop effective radiation countermeasures. Moreover, altered protein profiles serve as a crucial biomarkers for intestinal radiation damage. In this review, we present alterations in protein signatures following intestinal radiation damage as detected by proteomics approaches in preclinical and clinical models with the aim of providing a better understanding of how to accomplish intestinal protection against radiation damage.
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Affiliation(s)
- Enoch K. Larrey
- Division of Radiation Health, Department of Pharmaceutical Sciences, College of Pharmacy, University of Arkansas for Medical Sciences, 4301 W. Markham St., Little Rock, AR 72205, USA
- Department of Information Science, University of Arkansas at Little Rock, 2801 S University Ave, Little Rock, AR 72204, USA
| | - Rupak Pathak
- Division of Radiation Health, Department of Pharmaceutical Sciences, College of Pharmacy, University of Arkansas for Medical Sciences, 4301 W. Markham St., Little Rock, AR 72205, USA
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17
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Dainiak N, Albanese J. Medical management of acute radiation syndrome. JOURNAL OF RADIOLOGICAL PROTECTION : OFFICIAL JOURNAL OF THE SOCIETY FOR RADIOLOGICAL PROTECTION 2022; 42:031002. [PMID: 35767939 DOI: 10.1088/1361-6498/ac7d18] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/17/2022] [Accepted: 06/29/2022] [Indexed: 06/15/2023]
Abstract
Acute radiation syndrome (ARS) is a clinical syndrome involving four organ systems, resulting in the hematopoietic syndrome (HS), gastrointestinal subsyndrome (GIS), neurovascular subsyndrome (NVS) and cutaneous subsyndrome (CS). Since few healthcare providers have seen an ARS case, evidence-based recommendations are needed to guide medical management in a mass casualty scenario. The authors reviewed recommendations from evidence-based and narrative reviews by expert consultants to the World Health Organisation (WHO), a subsequent review of published HS cases, and infectious disease guidelines for management of febrile neutropenia. The WHO Consultancy applied a rigorous grading system to evaluate treatment strategies described in published ARS cases as of 2009, strategies to manage HS in unirradiated persons, results of ARS studies in animal models of ARS, and recommendations of prior expert panels. Major findings for HS were (a) no randomised controlled studies have been performed, (b) data are restricted by the lack of comparator groups, and (c) reports of countermeasures for management of injury to non-hematopoietic organs are often incomplete. Strength of recommendations ranged from strong to weak. Countermeasures of potential benefit include cytokines and for a subgroup of HS patients, hematopoietic stem cell transplantation. These recommendations did not change in a subsequent analysis of HS cases. Recommendations also included fluoroquinolones, bowel decontamination, serotonin receptor antagonists, loperamide and enteral nutrition for GIS; supportive care for NVS; and topical steroids, antihistamines and antibiotics, and surgical excision/grafting for CS. Also reviewed are critical care management guidelines, the role of mesenchymal stem cells for CS, the potential of a platelet-stimulating cytokine for HS, and the author's approach to clinical management of microbial infections associated with ARS based on published guidelines of infectious disease experts. Today's management of HS is supported by evidence-based guidelines. Management of non-HS subsyndromes is supported by a narrative review of the literature and recommendations of infectious disease societies.
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Affiliation(s)
- Nicholas Dainiak
- Department of Therapeutic Radiology, Yale University School of Medicine, 15 York Street, New Haven, CT 06520, United States of America
| | - Joseph Albanese
- Department of Therapeutic Radiology, Yale University School of Medicine, 15 York Street, New Haven, CT 06520, United States of America
- Center for Emergency Preparedness and Disaster Response, Yale New Haven Health, 99 Hawley Lane, Stratford, CT 06614, United States of America
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18
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Urban R, Wong J, Lim P, Zhang S, Spadinger I, Olson R, Bachand F, Ho C, Tinker AV, Gondara L, Hamilton SN. Cervical cancer patient reported gastrointestinal outcomes: intensity/volumetric modulated vs. 3D conformal radiation therapy. J Gynecol Oncol 2022; 33:e70. [PMID: 35882607 PMCID: PMC9428301 DOI: 10.3802/jgo.2022.33.e70] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2021] [Revised: 06/12/2022] [Accepted: 06/21/2022] [Indexed: 12/24/2022] Open
Abstract
OBJECTIVE To evaluate gastrointestinal (GI) patient reported outcomes (PROs) in cervical cancer patients treated with definitive radiotherapy (RT), comparing 3D conformal RT (3DCRT) vs. intensity modulated/volumetric modulated arc therapy (IMRT/VMAT). METHODS An analysis of patients treated with definitive RT between 2015-2018 was performed. GI PROs were prospectively collected at baseline, during RT (acute), ≤12 weeks after RT (subacute), and >12 weeks after RT (late). GI PROs evaluated three symptom domains: bowel problems (BPs), bowel bother (BB), and abdominal problems (APs). Multiple linear regression analysis was performed to investigate associations between mean changes of symptom scores with clinical and dosimetric variables. RESULTS The cohort included 167 patients. A total of 100 (60%) patients were treated with IMRT/VMAT and 67 (40%) with 3DCRT. In the subacute phase, the mean change of symptom scores from baseline in 3DCRT vs. IMRT/VMAT were +0.9 vs. -1.15 (p=0.004) for BP, +2.18 vs. -0.10 (p=0.019) for BB, and +1.41 vs. -0.38 (p=0.021) for AP. Likewise, in the late phase, mean changes were +0.72 vs. -0.82 (p=0.014) for BP, +1.98 vs. -0.03 (p=0.008) for BB, and +1.29 vs. -0.31 (p<0.001) for AP. On multiple linear regression, use of 3DCRT vs. IMRT/VMAT was associated with greater mean changes in subacute BP (p=0.023) and late phase AP (p=0.019). A higher small bowel V50Gy was associated increased symptom scores in late AP (p=0.012). CONCLUSION 3DCRT was associated with significantly greater worsening of GI PRO symptom scores in the subacute and late phase. These data support the ongoing use of IMRT/VMAT in routine practice.
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Affiliation(s)
- Ryan Urban
- Department of Medicine, The University of British Columbia, Vancouver, BC, Canada.,Department of Radiation Oncology, BC Cancer - Vancouver, Vancouver, BC, Canada
| | - Justin Wong
- Department of Medicine, The University of British Columbia, Vancouver, BC, Canada
| | - Peter Lim
- Department of Medicine, The University of British Columbia, Vancouver, BC, Canada.,Department of Radiation Oncology, BC Cancer - Vancouver, Vancouver, BC, Canada
| | - Susan Zhang
- Department of Medicine, The University of British Columbia, Vancouver, BC, Canada.,Department of Medical Physics, BC Cancer - Vancouver, Vancouver, BC, Canada
| | - Ingrid Spadinger
- Department of Medicine, The University of British Columbia, Vancouver, BC, Canada.,Department of Medical Physics, BC Cancer - Vancouver, Vancouver, BC, Canada
| | - Robert Olson
- Department of Medicine, The University of British Columbia, Vancouver, BC, Canada.,Department of Radiation Oncology, BC Cancer - Prince George, Prince George, BC, Canada
| | - Francois Bachand
- Department of Medicine, The University of British Columbia, Vancouver, BC, Canada.,Department of Radiation Oncology, BC Cancer - Kelowna, Kelowna, BC, Canada
| | - Clement Ho
- Department of Medicine, The University of British Columbia, Vancouver, BC, Canada.,Department of Radiation Oncology, BC Cancer - Surrey, Surrey, BC, Canada
| | - Anna V Tinker
- Department of Medicine, The University of British Columbia, Vancouver, BC, Canada.,Department of Medical Oncology, BC Cancer - Vancouver, Vancouver, BC, Canada
| | - Lovedeep Gondara
- Department of Population Oncology, BC Cancer - Vancouver, Vancouver, BC, Canada
| | - Sarah Nicole Hamilton
- Department of Medicine, The University of British Columbia, Vancouver, BC, Canada.,Department of Radiation Oncology, BC Cancer - Vancouver, Vancouver, BC, Canada.
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19
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Shen H, Han J, Liu C, Cao F, Huang Y. Grape Seed Proanthocyanidins Exert a Radioprotective Effect on the Testes and Intestines Through Antioxidant Effects and Inhibition of MAPK Signal Pathways. Front Med (Lausanne) 2022; 8:836528. [PMID: 35141259 PMCID: PMC8818786 DOI: 10.3389/fmed.2021.836528] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2021] [Accepted: 12/29/2021] [Indexed: 11/15/2022] Open
Abstract
The testes and intestines are highly sensitive to ionizing radiation. Low-dose radiation can cause infertility and enteritis. However, there is a lack of safe and efficient radioprotective agents. This study aims to investigate the radioprotective effects of grape seed proanthocyanidins (GSPs) on testicular and intestinal damage induced by ionizing radiation. In vitro, GSPs reduced the apoptosis and proliferation inhibition of mouse testicular stromal cells TM3 and human small intestinal crypt epithelial cells HIEC induced by ionizing radiation, and alleviated DNA double-strand breaks. In vivo, GSPs ameliorated the pathological damage of the testes and intestines induced by ionizing radiation, and protected the endocrine function of the testes and the barrier function of the intestines. In addition, we preliminarily proved that the radioprotective effect of GSPs is related to its antioxidant effect and inhibition of MAPK signaling pathways. Our results indicate that GSPs are expected to be a safe and effective radioprotective drug.
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Affiliation(s)
- Hui Shen
- Department of Central Laboratory, First Hospital of Jiaxing, Affiliated Hospital of Jiaxing University, Jiaxing, China
| | - Jun Han
- Department of Radiology, First Hospital of Jiaxing, Affiliated Hospital of Jiaxing University, Jiaxing, China
| | - Chunlei Liu
- Department of Radiation Oncology, Chifeng Municipal Hospital, Chifeng Clinical Medical School of Inner Mongolia Medical University, Chifeng, China
| | - Fei Cao
- Department of Radiotherapy, Changhai Hospital of Shanghai, First Affiliated Hospital of Naval Medical University, Shanghai, China
| | - Yijuan Huang
- Department of Radiology, First Hospital of Jiaxing, Affiliated Hospital of Jiaxing University, Jiaxing, China
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20
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Liu HX, Lu X, Zhao H, Li S, Gao L, Tian M, Liu QJ. Enhancement of Acylcarnitine Levels in Small Intestine of Abdominal Irradiation Rats Might Relate to Fatty Acid β-Oxidation Pathway Disequilibration. Dose Response 2022; 20:15593258221075118. [PMID: 35221822 PMCID: PMC8874182 DOI: 10.1177/15593258221075118] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2021] [Accepted: 12/24/2021] [Indexed: 11/21/2022]
Abstract
Objective This study aims to analyze the alteration of carnitine profile in the small intestine of abdominal irradiation-induced intestinal injury rats and explore the possible reason for the altered carnitine profile. Methods The abdomens of 15 male Sprague Dawley (SD) rats were irradiated with 0, 10, and 15 Gy of 60Co gamma rays. The carnitine profile in the small intestine and plasma samples of SD rats at 72 h after abdominal irradiated with 0 Gy or 10 Gy of 60Co gamma rays were measured by targeted metabolomics. The changes of fatty acid β-oxidation (FAO), including the expression of carnitine palmitoyltransferase 1 (CPT1) and acyl-CoA dehydrogenases, were analyzed in the small intestine samples of SD rats after exposed to 0, 10, and 15 Gy groups. Results There were eleven acylcarnitines in the small intestine and fourteen acylcarnitines in the plasma of the rat model significantly enhanced, respectively (P < .05). The expression level and activity of CPT1 in the small intestine were remarkably increased (P < .05), and the activity of acyl-CoA dehydrogenase in the small intestine was noticeably reduced (P < .01) after abdominal irradiation. Conclusion The enhanced acylcarnitine levels in the small intestine of abdominal irradiation rats might relate to the FAO pathway disequilibration.
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Affiliation(s)
- Hai-Xiang Liu
- China CDC Key Laboratory of Radiological Protection and Nuclear Emergency, National Institute for Radiological Protection, Chinese Center for Disease Control and Prevention, Beijing, China
| | - Xue Lu
- China CDC Key Laboratory of Radiological Protection and Nuclear Emergency, National Institute for Radiological Protection, Chinese Center for Disease Control and Prevention, Beijing, China
| | - Hua Zhao
- China CDC Key Laboratory of Radiological Protection and Nuclear Emergency, National Institute for Radiological Protection, Chinese Center for Disease Control and Prevention, Beijing, China
| | - Shuang Li
- China CDC Key Laboratory of Radiological Protection and Nuclear Emergency, National Institute for Radiological Protection, Chinese Center for Disease Control and Prevention, Beijing, China
| | - Ling Gao
- China CDC Key Laboratory of Radiological Protection and Nuclear Emergency, National Institute for Radiological Protection, Chinese Center for Disease Control and Prevention, Beijing, China
| | - Mei Tian
- China CDC Key Laboratory of Radiological Protection and Nuclear Emergency, National Institute for Radiological Protection, Chinese Center for Disease Control and Prevention, Beijing, China
| | - Qing-Jie Liu
- China CDC Key Laboratory of Radiological Protection and Nuclear Emergency, National Institute for Radiological Protection, Chinese Center for Disease Control and Prevention, Beijing, China
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Nie H, Pan J, An F, Zheng C, Zhang Q, Zhan Q. Comprehensive Analysis of Serum Metabolites Profiles in Acute Radiation Enteritis Rats by Untargeted Metabolomics. TOHOKU J EXP MED 2021; 255:257-265. [PMID: 34853247 DOI: 10.1620/tjem.255.257] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
Abstract
Acute radiation enteritis is a common complication occurring in patients with pelvic and abdominal tumors who receive radiotherapy. Acute radiation enteritis seriously reduces the life quality, even threatens the lives of patients. Untargeted metabolomics is an emerging strategy to explore the novel biomarkers and uncover potential pathogenesis of acute radiation enteritis. Acute radiation enteritis rat model was established by single abdominal irradiation with a gamma-ray dose of 10 Gy. Serum from 15 acute radiation enteritis rats and 10 controls was extracted for metabolomics analysis by UHPLC-Q-TOF/MS. Clinical manifestations and morphological alterations of intestine confirmed the successful establishment of acute radiation enteritis. According to the metabolomics data, 6,044 positive peaks and 4,241 negative peaks were extracted from each specimen. OPLS-DA analysis and the heat map for cluster analysis showed satisfactory discriminatory power between acute radiation enteritis rats and controls. Subsequent analysis extracted 66 significantly differentially expressed metabolites, which might be potential biomarkers for acute radiation enteritis diagnosis. Moreover, Kyoto Encyclopedia of Genes and Genomes enrichment analyses uncovered the potential mechanisms through which differentially expressed metabolites participated in acute radiation enteritis pathogenesis. To sum up, we summarized several differentially expressed serum metabolites as potential biomarkers for diagnosis of acute radiation enteritis and provide latent clues for elucidating acute radiation enteritis pathology.
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Affiliation(s)
- He Nie
- Department of Gastroenterology, Wuxi People's Hospital Affiliated to Nanjing Medical University
| | - Jiadong Pan
- Department of Gastroenterology, Wuxi People's Hospital Affiliated to Nanjing Medical University
| | - Fangmei An
- Department of Gastroenterology, Wuxi People's Hospital Affiliated to Nanjing Medical University
| | - Chuwei Zheng
- Department of Gastroenterology, Wuxi People's Hospital Affiliated to Nanjing Medical University
| | - Qinglin Zhang
- Department of Gastroenterology, Wuxi People's Hospital Affiliated to Nanjing Medical University
| | - Qiang Zhan
- Department of Gastroenterology, Wuxi People's Hospital Affiliated to Nanjing Medical University
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22
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Pacevicius J, Petrauskas V, Pilipavicius L, Dulskas A. Local Excision ± Chemoradiotherapy vs. Total Mesorectal Excision for Early Rectal Cancer: Case-Matched Analysis of Long-Term Results. Front Surg 2021; 8:746784. [PMID: 34733880 PMCID: PMC8558343 DOI: 10.3389/fsurg.2021.746784] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2021] [Accepted: 09/07/2021] [Indexed: 12/14/2022] Open
Abstract
Background: Our aim was to compare the bowel function and oncologic outcomes following these two treatment modalities. Materials and methods: This was a single-center study with 67 patients included between 2009 and 2018. A total of 32 patients underwent total mesorectal excision (TME) group and 35 transanal local excisions (LE) ± chemoradiation. We performed a case-matched analysis: we matched the patients by age, cancer stage, and comorbidities. Duration of operation, postoperative complications, length of hospital stay, and long-term functional and oncological outcomes were compared. We calculated oncological outcomes using Kaplan-Meier Cox diagrams. In addition, we used a low anterior resection syndrome (LARS) score for the bowel function assessment. Results: Mean operation time in the LE group was 58.8 ± 45 min compared with the TME group that was 121.1 ± 42 min (p = 0.032). Complications were seen in 5.7% in LE group and 15.62% in TME group (p = 0.043). ~85.2% of the patients had no LARS in LE group compared with 54.5% in TME group (p = 0.018). Minor LARS was 7.4% in LE group compared with 31.8% in TME group (p = 0.018); major LARS was 7.4 and 13.7%, respectively (p = 0.474). Hospital stay was 2.77 days in LE group compared with 9.21 days in TME group (p = 0.036). The overall survival was 68.78 months in LE group compared with 74.81 months in TME group (p = 0.964). Conclusion: Our results of a small sample size showed that local excision ± chemoradiation is a rather safe method for early rectal cancer compared with gold standard treatment. In addition, better bowel function is preserved with less postoperative complications and shorter hospital stays.
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Affiliation(s)
- Julius Pacevicius
- Department of Abdominal and General Surgery and Oncology, National Cancer Institute, Vilnius, Lithuania
| | - Vidas Petrauskas
- Department of Abdominal and General Surgery and Oncology, National Cancer Institute, Vilnius, Lithuania
| | - Lukas Pilipavicius
- Department of Abdominal and General Surgery and Oncology, National Cancer Institute, Vilnius, Lithuania
| | - Audrius Dulskas
- Department of Abdominal and General Surgery and Oncology, National Cancer Institute, Vilnius, Lithuania
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Fernandes A, Oliveira A, Soares R, Barata P. The Effects of Ionizing Radiation on Gut Microbiota, a Systematic Review. Nutrients 2021; 13:3025. [PMID: 34578902 PMCID: PMC8465723 DOI: 10.3390/nu13093025] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2021] [Revised: 08/20/2021] [Accepted: 08/26/2021] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND The human gut microbiota is defined as the microorganisms that collectively inhabit the intestinal tract. Its composition is relatively stable; however, an imbalance can be precipitated by various factors and is known to be associated with various diseases. Humans are daily exposed to ionizing radiation from ambient and medical procedures, and gastrointestinal side effects are not rare. METHODS A systematic search of PubMed, EMBASE, and Cochrane Library databases was conducted. Primary outcomes were changes in composition, richness, and diversity of the gut microbiota after ionizing radiation exposure. Standard methodological procedures expected by Cochrane were used. RESULTS A total of 2929 nonduplicated records were identified, and based on the inclusion criteria, 11 studies were considered. Studies were heterogeneous, with differences in population and outcomes. Overall, we found evidence for an association between ionizing radiation exposure and dysbiosis: reduction in microbiota diversity and richness, increase in pathogenic bacteria abundance (Proteobacteria and Fusobacteria), and decrease in beneficial bacteria (Faecalibacterium and Bifidobacterium). CONCLUSIONS This review highlights the importance of considering the influence of ionizing radiation exposure on gut microbiota, especially when considering the side effects of abdominal and pelvic radiotherapy. Better knowledge of these effects, with larger population studies, is needed.
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Affiliation(s)
- Ana Fernandes
- Department of Nuclear Medicine, Centro Hospitalar Universitário de São João, E.P.E., 4200-319 Porto, Portugal;
| | - Ana Oliveira
- Department of Nuclear Medicine, Centro Hospitalar Universitário de São João, E.P.E., 4200-319 Porto, Portugal;
| | - Raquel Soares
- Department of Biomedicine, Faculdade de Medicina da Universidade do Porto, 4200-319 Porto, Portugal;
- i3S, Instituto de Investigação e Inovação em Saúde, Universidade do Porto, 4200-135 Porto, Portugal;
| | - Pedro Barata
- i3S, Instituto de Investigação e Inovação em Saúde, Universidade do Porto, 4200-135 Porto, Portugal;
- Department of Pharmaceutical Science, Faculdade de Ciências da Saúde da Universidade Fernando Pessoa, 4249-004 Porto, Portugal
- Department of Pathology, Centro Hospitalar Universitário do Porto, 4099-001 Porto, Portugal
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Afifi ANAM, Powerski M, Jechorek D, Brunner TB, Weigt J, Venerito M. Radiation-induced damage in the upper gastrointestinal tract: clinical presentation, diagnostic tests and treatment options. Best Pract Res Clin Gastroenterol 2020; 48-49:101711. [PMID: 33317797 DOI: 10.1016/j.bpg.2020.101711] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/29/2020] [Revised: 11/05/2020] [Accepted: 11/09/2020] [Indexed: 01/31/2023]
Abstract
Radiation-induced damage of the upper gastrointestinal (GI) tract results from radiation of GI tumors or structures adjacent to the GI tract. Radiation-induced damages of the upper GI tract may be acute or delayed, and ranges from lack of appetite, mucosal inflammation (i.e. esophagitis, gastritis, duodenitis) to ulcers, which may be complicated by perforation, penetration, bleeding and stenosis. Radiation-related factors as well as individual patient predisposing factors may increase susceptibility to post-radiation damage. High quality evidence for the treatment of radiation-induced GI damage is scarce and the management is often extrapolated from studies on GI lesions of different etiology. Treatment depends on severity and localization of the radiation-induced damage, and ranges from supportive and dietary measures to endoscopic interventions or surgery. Modern radiation techniques may decrease the incidence and severity of the radiation-induced upper gastrointestinal disease.
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Affiliation(s)
- Ahmed N A M Afifi
- Universitätsklinik für Gastroenterologie, Hepatologie und Infektiologie, Germany
| | - Maciej Powerski
- Universitätsklinik für Radiologie und Nuklearmedizin, Germany
| | | | - Thomas B Brunner
- Universitätsklinik für Strahlentherapie, Otto-von-Guericke Universitätsklinikum Magdeburg, Germany
| | - Jochen Weigt
- Universitätsklinik für Gastroenterologie, Hepatologie und Infektiologie, Germany
| | - Marino Venerito
- Universitätsklinik für Gastroenterologie, Hepatologie und Infektiologie, Germany.
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25
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Gupta N, Kainthola A, Tiwari M, Agrawala PK. Gut microbiota response to ionizing radiation and its modulation by HDAC inhibitor TSA. Int J Radiat Biol 2020; 96:1560-1570. [PMID: 33001776 DOI: 10.1080/09553002.2020.1830317] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Abstract
AIM Trichostatin A (TSA) has been shown to mitigate whole body γ-radiation-induced morbidity and mortality. The current study aimed at studying the effects of TSA post-irradiation treatment on gut-microbiota, especially the translocation of the microbes from the intestine to other organs in C57 Bl/6 mice model. MATERIALS AND METHODS On 1st, 3rd 5th 7th 9th 12th and 14th days after various treatments bacteria were isolated from the intestine and nearby organs (mesenteric lymph node, spleen and liver) for further analysis. The jejunum part of all animals was processed for histological analysis. RESULTS The group radiation + drug showed reduced susceptibility to radiation injury as well as microbiota related anomalies compared to the irradiated alone group. This was described by increased microflora in different parts of the GI tract in the radiation + drug group compared to the irradiated group and reduced histopathological damages in the jejunum. Also, a reduced percentage of translocated bacteria were found in different organs of radiation + drug group animals. CONCLUSION TSA treatment post-irradiation could effectively control bacterial translocation as well as GI injury in mice.
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Affiliation(s)
- Noopur Gupta
- Department of Radiation Genetics and Epigenetics, Institute of Nuclear Medicine and Allied Sciences, Delhi, India.,Ambedkar Center for Biomedical Research, University of Delhi, Delhi, India
| | - Anup Kainthola
- Department of Radiation Genetics and Epigenetics, Institute of Nuclear Medicine and Allied Sciences, Delhi, India
| | - Manisha Tiwari
- Ambedkar Center for Biomedical Research, University of Delhi, Delhi, India
| | - Paban K Agrawala
- Department of Radiation Genetics and Epigenetics, Institute of Nuclear Medicine and Allied Sciences, Delhi, India
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26
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Sittipo P, Pham HQ, Park CE, Kang GU, Zhi Y, Ji HJ, Jang A, Seo HS, Shin JH, Lee YK. Irradiation-Induced Intestinal Damage Is Recovered by the Indigenous Gut Bacteria Lactobacillus acidophilus. Front Cell Infect Microbiol 2020; 10:415. [PMID: 32974214 PMCID: PMC7461978 DOI: 10.3389/fcimb.2020.00415] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2020] [Accepted: 07/07/2020] [Indexed: 12/12/2022] Open
Abstract
The intestinal tract is one of the most sensitive organs following irradiation. The protective effect of specific indigenous microbiota on irradiation-induced damage to intestinal epithelial cells has not been reported. Mice were irradiated with a single dose of 6 Gy of gamma rays. The intestinal damage was analyzed by histopathology. Intestinal stemness and differentiation were determined by intestinal organoid culture. Microbiota community was observed by high-throughput 16S rRNA gene sequencing and oligotyping analysis. We showed that distal small intestine was damaged by sublethal dose of gamma irradiation. Intestinal organoids derived from the irradiated mice showed defects in budding and mucin expression, suggesting the detrimental effect of irradiation on the intestinal stemness and differentiation. In addition, irradiation reduced intestinal immunoglobulin A level, concomitant with decreased microbiota diversity based on our high-throughput 16S rRNA gene sequencing data. Especially, the relative abundance of Lactobacillus was reduced at early time point post-irradiation; however, it was recovered at late time point. Oligotyping analysis within the Lactobacillus genus indicated that Lactobacillus-related oligotype 1 (OT1) including Lactobacillus acidophilus might drive recovery after irradiation as it was associated with increased long-term numbers post-exposure. We showed that treatment with heat-killed L. acidophilus rescued the budding-impaired organoids and induced sufficient differentiation in epithelial cells, and particularly mucin-producing cells, in intestinal organoids. This study provides the first evidence that the indigenous gut bacteria L. acidophilus enhance intestinal epithelial function with respect to irradiation-induced intestinal damage by improving intestinal stem cell function and cell differentiation.
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Affiliation(s)
- Panida Sittipo
- Department of Integrated Biomedical Science, Soonchunhyang Institute of Medi-Bio Science, Soonchunhyang University, Cheonan, South Korea
| | - Huy Quang Pham
- Department of Applied Biosciences, Kyungpook National University, Daegu, South Korea
| | - Chang Eon Park
- Department of Applied Biosciences, Kyungpook National University, Daegu, South Korea
| | - Gi-Ung Kang
- Department of Applied Biosciences, Kyungpook National University, Daegu, South Korea
| | - Yong Zhi
- Radiation Biotechnology Research Division, Advanced Radiation Technology Institute, Korea Atomic Energy Research Institute, Jeongeup, South Korea
| | - Hyun Jung Ji
- Radiation Biotechnology Research Division, Advanced Radiation Technology Institute, Korea Atomic Energy Research Institute, Jeongeup, South Korea
| | - Ayeung Jang
- Radiation Biotechnology Research Division, Advanced Radiation Technology Institute, Korea Atomic Energy Research Institute, Jeongeup, South Korea
| | - Ho Seong Seo
- Radiation Biotechnology Research Division, Advanced Radiation Technology Institute, Korea Atomic Energy Research Institute, Jeongeup, South Korea
| | - Jae-Ho Shin
- Department of Applied Biosciences, Kyungpook National University, Daegu, South Korea
| | - Yun Kyung Lee
- Department of Integrated Biomedical Science, Soonchunhyang Institute of Medi-Bio Science, Soonchunhyang University, Cheonan, South Korea
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Sadeghi H, Bagheri H, Shekarchi B, Javadi A, Najafi M. Mitigation of Radiation-Induced Gastrointestinal System Injury by Melatonin: A Histopathological Study. Curr Drug Res Rev 2020; 12:72-79. [PMID: 32578524 DOI: 10.2174/2589977511666191031094625] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2019] [Revised: 10/04/2019] [Accepted: 10/15/2019] [Indexed: 06/11/2023]
Abstract
AIMS The current study aimed to investigate the potential role of melatonin in the mitigation of radiation-induced gastrointestinal injury. BACKGROUND Organs of the gastrointestinal system such as the intestines, colon, duodenum, ileum etc. are sensitive to ionizing radiation. Mitigation of radiation-induced gastrointestinal injury is an interesting topic in radiobiology and a life-saving approach for exposed persons after a radiation event or improving the quality of life of radiotherapy patients. OBJECTIVE The study aimed to find the possible mitigation effect of melatonin on radiation-induced damage to the small and large intestines. METHODS 40 male mice were randomly assigned into four groups namely G1: control, G2: melatonin treatment, G3: whole-body irradiation, and G4: melatonin treatment after whole-body irradiation. A cobalt-60 gamma-ray source was used to deliver 7 Gy to the whole body. 100 mg/kg melatonin was administered orally 24 h after irradiation and continued for 5 days. Thirty days after irradiation, histopathological evaluations were performed. RESULTS The whole-body irradiation led to remarkable inflammation, villi shortening, apoptosis and damage to goblet cells of the small intestine. Furthermore, moderate to severe inflammation, apoptosis, congestion, crypt injury and goblet cell damage were reported for the colon. Treatment with melatonin after whole-body irradiation led to significant mitigation of radiation toxicity in both small and large intestines. CONCLUSION Melatonin could mitigate intestinal injury following whole-body exposure to radiation. Treatment with melatonin after an accidental exposure to radiation may increase survival via mitigation of damages to radiosensitive organs, including the gastrointestinal system.
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Affiliation(s)
- Hossein Sadeghi
- AJA Radiation Sciences Radiation Sciences (ARSRC), Tehran, Iran
| | - Hamed Bagheri
- AJA Radiation Sciences Radiation Sciences (ARSRC), Tehran, Iran
| | - Babak Shekarchi
- AJA Radiation Sciences Radiation Sciences (ARSRC), Tehran, Iran
| | - Abdolreza Javadi
- Department of Pathology, Imam Hossein Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Masoud Najafi
- Radiology and Nuclear Medicine Department, School of Paramedical Sciences, Kermanshah University of Medical Sciences, Kermanshah, Iran
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Yang L, Yuan J, Zeng X, Xi M, Wang H. The outcomes and quality of life of young patients undergoing adjuvant radiotherapy versus non-radiotherapy following surgery treating early FIGO stage cervical squamous cell cancer in southwestern China. Sci Rep 2020; 10:9583. [PMID: 32533117 PMCID: PMC7293287 DOI: 10.1038/s41598-020-66661-y] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2019] [Accepted: 05/22/2020] [Indexed: 12/24/2022] Open
Abstract
BACKGROUND The incidence of cervical cancer in young women is rising, and squamous cell carcinoma makes up a great percentage of the histological types. The presence of aggressive pathologic risk factors following patients' primary surgery may warrant the use of adjuvant radiotherapy. It is important to weigh up the risks and benefits of using adjuvant radiotherapy for each young patient so as to maximize their prognosis while minimizing the treatment-related morbidity. METHODS A retrospective study was performed. It consisted of 97 patients under 35 years old who were diagnosed with cervical squamous cell carcinoma and underwent treatment at West China Second University Hospital between December 2009 and January 2014. Five-year follow-up, prognostic risks, long-term radiation toxicity, female sexual function, and quality of life were investigated. RESULTS Adjuvant radiotherapy did improve the prognosis of young patients with lymph node metastases. However, there were few significant differences in progress-free survival and overall survival for the young patients without lymph node metastases following adjuvant radiotherapy. Besides, young patients who took radiotherapy exhibited greater intestinal dysfunction, more severe lower extremities edema, greater sexual dysfunction, and worse long-term quality of life. CONCLUSION Young patients with early-stage cervical squamous cell carcinoma without lymph node metastases who have undergone the primary surgery should be counseled in detail before the decision to use adjuvant radiotherapy can be made. The counseling should emphasize not only the benefit that local recurrence rates can be reduced, but also the risks that treatment-related side effects could increase and lower QoL could occur.
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Affiliation(s)
- Lingyun Yang
- Department of Obstetrics and Gynecology, West China Second University Hospital, Chengdu, China
- Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, Chengdu, China
| | - Jialing Yuan
- Department of Obstetrics and Gynecology, West China Second University Hospital, Chengdu, China
- Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, Chengdu, China
| | - Xi Zeng
- Department of Obstetrics and Gynecology, West China Second University Hospital, Chengdu, China
- Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, Chengdu, China
| | - Mingrong Xi
- Department of Obstetrics and Gynecology, West China Second University Hospital, Chengdu, China
- Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, Chengdu, China
| | - Hongjing Wang
- Department of Obstetrics and Gynecology, West China Second University Hospital, Chengdu, China.
- Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, Chengdu, China.
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29
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Miousse IR, Ewing LE, Skinner CM, Pathak R, Garg S, Kutanzi KR, Melnyk S, Hauer-Jensen M, Koturbash I. Methionine dietary supplementation potentiates ionizing radiation-induced gastrointestinal syndrome. Am J Physiol Gastrointest Liver Physiol 2020; 318:G439-G450. [PMID: 31961718 PMCID: PMC7099489 DOI: 10.1152/ajpgi.00351.2019] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Methionine is an essential amino acid needed for a variety of processes in living organisms. Ionizing radiation depletes tissue methionine concentrations and leads to the loss of DNA methylation and decreased synthesis of glutathione. In this study, we aimed to investigate the effects of methionine dietary supplementation in CBA/CaJ mice after exposure to doses ranging from 3 to 8.5 Gy of 137Cs of total body irradiation. We report that mice fed a methionine-supplemented diet (MSD; 19.5 vs. 6.5 mg/kg in a methionine-adequate diet, MAD) developed acute radiation toxicity at doses as low as 3 Gy. Partial body irradiation performed with hindlimb shielding resulted in a 50% mortality rate in MSD-fed mice exposed to 8.5 Gy, suggesting prevalence of radiation-induced gastrointestinal syndrome in the development of acute radiation toxicity. Analysis of the intestinal microbiome demonstrated shifts in the gut ecology, observed along with the development of leaky gut syndrome and bacterial translocation into the liver. Normal gut physiology impairment was facilitated by alterations in the one-carbon metabolism pathway and was exhibited as decreases in circulating citrulline levels mirrored by decreased intestinal mucosal surface area and the number of surviving crypts. In conclusion, we demonstrate that a relevant excess of methionine dietary intake exacerbates the detrimental effects of exposure to ionizing radiation in the small intestine.NEW & NOTEWORTHY Methionine supplementation, instead of an anticipated health-promoting effect, sensitizes mice to gastrointestinal radiation syndrome. Mechanistically, excess of methionine negatively affects intestinal ecology, leading to a cascade of physiological, biochemical, and molecular alterations that impair normal gut response to a clinically relevant genotoxic stressor. These findings speak toward increasing the role of registered dietitians during cancer therapy and the necessity of a solid scientific background behind the sales of dietary supplements and claims regarding their benefits.
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Affiliation(s)
- Isabelle R. Miousse
- 1Department of Environmental and Occupation Health, Fay W. Boozman College of Public Health, University of Arkansas for Medical Sciences, Little Rock, Arkansas,2Department of Biochemistry, College of Medicine, University of Arkansas for Medical Sciences, Little Rock, Arkansas
| | - Laura E. Ewing
- 1Department of Environmental and Occupation Health, Fay W. Boozman College of Public Health, University of Arkansas for Medical Sciences, Little Rock, Arkansas,3Department of Pharmacology and Toxicology, College of Medicine, University of Arkansas for Medical Sciences, Little Rock, Arkansas
| | - Charles M. Skinner
- 1Department of Environmental and Occupation Health, Fay W. Boozman College of Public Health, University of Arkansas for Medical Sciences, Little Rock, Arkansas,4Center for Dietary Supplements Research, Fay W. Boozman College of Public Health, University of Arkansas for Medical Sciences, Little Rock, Arkansas
| | - Rupak Pathak
- 5Division of Radiation Health, Department of Pharmaceutical Sciences, College of Pharmacy, University of Arkansas for Medical Sciences, Little Rock, Arkansas
| | - Sarita Garg
- 5Division of Radiation Health, Department of Pharmaceutical Sciences, College of Pharmacy, University of Arkansas for Medical Sciences, Little Rock, Arkansas
| | - Kristy R. Kutanzi
- 1Department of Environmental and Occupation Health, Fay W. Boozman College of Public Health, University of Arkansas for Medical Sciences, Little Rock, Arkansas
| | - Stepan Melnyk
- 6Arkansas Children’s Research Institute, Little Rock, Arknsas
| | - Martin Hauer-Jensen
- 5Division of Radiation Health, Department of Pharmaceutical Sciences, College of Pharmacy, University of Arkansas for Medical Sciences, Little Rock, Arkansas
| | - Igor Koturbash
- 1Department of Environmental and Occupation Health, Fay W. Boozman College of Public Health, University of Arkansas for Medical Sciences, Little Rock, Arkansas,4Center for Dietary Supplements Research, Fay W. Boozman College of Public Health, University of Arkansas for Medical Sciences, Little Rock, Arkansas
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30
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Zimmermann F. Gastrointestinal Toxicity. Radiat Oncol 2020. [DOI: 10.1007/978-3-319-52619-5_108-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
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31
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Lindgren A, Dunberger G, Steineck G, Bergmark K, Enblom A. Identifying female pelvic cancer survivors with low levels of physical activity after radiotherapy: women with fecal and urinary leakage need additional support. Support Care Cancer 2019; 28:2669-2681. [PMID: 31641868 PMCID: PMC7181502 DOI: 10.1007/s00520-019-05033-3] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2019] [Accepted: 08/08/2019] [Indexed: 12/17/2022]
Abstract
Objective To investigate the frequency of physical activity among female pelvic cancer survivors (i.e., gynecological, rectal, and anal cancer survivors) and to investigate if survivors who practiced physical activity less than once a week differed from survivors practicing physical activity at least once a week with respect to urinary and fecal leakage, clinical and sociodemographic characteristics, quality of life (QoL), and depressed and anxious mood. Methods Female pelvic cancer survivors (n = 578, mean age 64 years) answered a questionnaire 6–48 months after radiotherapy. A multivariable regression model analyzed factors covarying with frequency of physical activity. We compared QoL and depressed and anxious mood between women practicing physical activity at least or less than once a week. Results Of 568 women delivering data, 186 (33%) practiced physical activity less than once a week while 382 (67%) practiced physical activity at least weekly. Women who leaked a large or all volume of stools (p = 0.01), had just elementary school level of education (p < 0.001), smokers (p = 0.049), or had lymphedema without receiving lymphedema treatment (p = 0.030) were more likely to practice physical activity less than weekly (50%, 45%, 45%, and 37%, respectively) compared with other women. Women practicing physical activity at least weekly reported better QoL (p < 0.001) and lower frequency of depressed mood (p = 0.044) compared with the others. Conclusions Female cancer survivors experiencing fecal leakage were less likely to practice weekly physical activity than survivors without leakage. The survivors practicing weekly physical activity experienced better QoL and experienced depressed mood less frequently than the others.
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Affiliation(s)
- Anna Lindgren
- County Council of Östergötland and Department of Medical and Health Sciences, Division of Physiotherapy, Linköping University, SE-58183, Linköping, Sweden.
| | - G Dunberger
- Department of Health Care Sciences, Ersta Sköndal University College, Stockholm, Sweden
| | - G Steineck
- Department of Oncology-Pathology, Division of Clinical Cancer Epidemiology, Karolinska Institute, Stockholm, Sweden.,Department of Clinical Sciences, Division of Clinical Cancer Epidemiology, Sahlgrenska Academy, Gothenburg University, Gothenburg, Sweden
| | - K Bergmark
- Department of Clinical Sciences, Division of Clinical Cancer Epidemiology, Sahlgrenska Academy, Gothenburg University, Gothenburg, Sweden
| | - A Enblom
- County Council of Östergötland, Activity and Health and Division of Coordinated Cancer Evaluation, Department of Medical and Health Sciences, Linköping University, Linköping, Sweden
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32
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Li XD, Wang Z, Wang XR, Shao D, Zhang X, Li L, Ge MF, Chang ZM, Dong WF. Berberine-loaded Janus gold mesoporous silica nanocarriers for chemo/radio/photothermal therapy of liver cancer and radiation-induced injury inhibition. Int J Nanomedicine 2019; 14:3967-3982. [PMID: 31239666 PMCID: PMC6554520 DOI: 10.2147/ijn.s206044] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2019] [Accepted: 04/13/2019] [Indexed: 12/21/2022] Open
Abstract
Background: The combination of chemotherapy with radiotherapy serves as a common therapeutic strategy in clinics. However, it is unsatisfactory due to its poor therapeutic efficiency and severe side-effects originating from chemotherapy-exerted systemic toxicity as well as radiation-induced injury. Purpose: Hence, Berberine (Ber), an isoquinolin alkaloid with low toxicity and protective effects against radiotherapy, was used as a novel chemotherapeutic agent for chemo-radiotherapy of liver cancer. Patients and methods: We preloaded Ber into folic acid targeting Janus gold mesoporous silica nanocarriers (FA-JGMSNs) for overcoming the poor bioavailability of Ber. Furthermore, FA-JGMSNs were not only employed as radiosensitizers for expanding radiotherapeutic effect, but also used as photothermal agents for supplementing chemo-radiotherapeutic effect by local photothermal therapy. Results: In vitro and in vivo experiemtal results demonstrated the highly efficient anti-tumor effect, good biosafety as well as the effective protection of normal tissue of this nanoplatform. Conclusion: Based on its superb performance, we believe our work provided a feasible strategy for triple-therapies of liver cancer.
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Affiliation(s)
- Xiao-Dong Li
- CAS Key Laboratory of Bio-Medical Diagnostics, Suzhou Institute of Biomedical Engineering and Technology, Chinese Academy of Sciences, Suzhou215163, People’s Republic of China
- University of Chinese Academy of Sciences, Beijing100049, People’s Republic of China
- Department of Echocardiography, The First Hospital of Jilin University, Changchun130021, People’s Republic of China
| | - Zheng Wang
- CAS Key Laboratory of Bio-Medical Diagnostics, Suzhou Institute of Biomedical Engineering and Technology, Chinese Academy of Sciences, Suzhou215163, People’s Republic of China
- University of Chinese Academy of Sciences, Beijing100049, People’s Republic of China
| | - Xin-Rui Wang
- Department of Hepatology, The First Hospital of Jilin University, Changchun130021, People’s Republic of China
| | - Dan Shao
- CAS Key Laboratory of Bio-Medical Diagnostics, Suzhou Institute of Biomedical Engineering and Technology, Chinese Academy of Sciences, Suzhou215163, People’s Republic of China
| | - Xi Zhang
- Department of Rheumatology, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou510630, People’s Republic of China
| | - Li Li
- CAS Key Laboratory of Bio-Medical Diagnostics, Suzhou Institute of Biomedical Engineering and Technology, Chinese Academy of Sciences, Suzhou215163, People’s Republic of China
| | - Ming-Feng Ge
- CAS Key Laboratory of Bio-Medical Diagnostics, Suzhou Institute of Biomedical Engineering and Technology, Chinese Academy of Sciences, Suzhou215163, People’s Republic of China
| | - Zhi-Min Chang
- CAS Key Laboratory of Bio-Medical Diagnostics, Suzhou Institute of Biomedical Engineering and Technology, Chinese Academy of Sciences, Suzhou215163, People’s Republic of China
| | - Wen-Fei Dong
- CAS Key Laboratory of Bio-Medical Diagnostics, Suzhou Institute of Biomedical Engineering and Technology, Chinese Academy of Sciences, Suzhou215163, People’s Republic of China
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Cheng S, He B, Zeng X. Prediction of anastomotic leakage after anterior rectal resection. Pak J Med Sci 2019; 35:830-835. [PMID: 31258603 PMCID: PMC6572974 DOI: 10.12669/pjms.35.3.252] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2018] [Accepted: 04/08/2019] [Indexed: 01/03/2023] Open
Abstract
OBJECTIVE Anastomotic Leakage (AL) is one of the most common complications after resection of rectal cancer. Recognition of the incidence and risk factors related to AL is important. This study aimed develops a model that can predict anastomotic leakage after anterior rectal resection. METHODS Data from 188 patients undergoing anterior resection of rectal cancer were collected for retrospective analysis. Patients were randomly divided in the development set and validation set at a 1:1 ratio. We first included age, sex, preoperative chemoradiotherapy, tumor size, degree of tumor differentiation, stage, TNM stage, lymph vascular invasion, distance, anastomotic method, diabetes, intraoperative time, intraoperative bleeding and smoking as candidates for variable selection with a LASSO method. A ROC curve was constructed with the validation set to assess the accuracy of the prediction model. RESULTS AL occurred in 20 of 188 patients (10.6%). Preoperative chemoradiotherapy (p=0.04), medium degree of tumor differentiation (p=0.04), anastomotic method (p<0.01), intraoperative bleeding≥400ml (p<0.01), smoking (p<0.01), diabetes (p<0.01) were significantly related to AL. The area under the ROC curve of the prediction model is 0.952. CONCLUSIONS This study developed a model that can predict anastomotic leakage after anterior rectal resection, which may aid the selection of preventive ileostomy and postoperative management.
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Affiliation(s)
- Shubang Cheng
- Dr. Shubang Cheng, MD, Department of Gastrointestinal, People’s Hospital of Longhua District, Affiliated Hospital of Guangdong Medical University, Shenzhen, Guangdong Province, China
| | - Bolin He
- Dr. Bolin He, MD, Department of Gastrointestinal, People’s Hospital of Longhua District, Affiliated Hospital of Guangdong Medical University, Shenzhen, Guangdong Province, China
| | - Xueyi Zeng
- Dr. Xueyi Zeng, MD, Department of Gastrointestinal, People’s Hospital of Longhua District, Affiliated Hospital of Guangdong Medical University, Shenzhen, Guangdong Province, China
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Van de Putte D, Demarquay C, Van Daele E, Moussa L, Vanhove C, Benderitter M, Ceelen W, Pattyn P, Mathieu N. Adipose-Derived Mesenchymal Stromal Cells Improve the Healing of Colonic Anastomoses Following High Dose of Irradiation Through Anti-Inflammatory and Angiogenic Processes. Cell Transplant 2018; 26:1919-1930. [PMID: 29390877 PMCID: PMC5802630 DOI: 10.1177/0963689717721515] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Cancer patients treated with radiotherapy (RT) could develop severe late side effects that affect their quality of life. Long-term bowel complications after RT are mainly characterized by a transmural fibrosis that could lead to intestinal obstruction. Today, surgical resection is the only effective treatment. However, preoperative RT increases the risk of anastomotic leakage. In this study, we attempted to use mesenchymal stromal cells from adipose tissue (Ad-MSCs) to improve colonic anastomosis after high-dose irradiation. MSCs were isolated from the subcutaneous fat of rats, amplified in vitro, and characterized by flow cytometry. An animal model of late radiation side effects was induced by local irradiation of the colon. Colonic anastomosis was performed 4 wk after irradiation. It was analyzed another 4 wk later (i.e., 8 wk after irradiation). The Ad-MSC-treated group received injections several times before and after the surgical procedure. The therapeutic benefit of the Ad-MSC treatment was determined by colonoscopy and histology. The inflammatory process was investigated using Fluorine-182-Fluoro-2-Deoxy-d-Glucose Positron Emission Tomography and Computed Tomography (18F-FDG-PET/CT) imaging and macrophage infiltrate analyses. Vascular density was assessed using immunohistochemistry. Results show that Ad-MSC treatment reduces ulcer size, increases mucosal vascular density, and limits hemorrhage. We also determined that 1 Ad-MSC injection limits the inflammatory process, as evaluated through 18F-FDG-PET-CT (at 4 wk), with a greater proportion of type 2 macrophages after iterative cell injections (8 wk). In conclusion, Ad-MSC injections promote anastomotic healing in an irradiated colon through enhanced vessel formation and reduced inflammation. This study also determined parameters that could be improved in further investigations.
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Affiliation(s)
- Dirk Van de Putte
- 1 Department of Pediatric and Gastrointestinal Surgery, Ghent University Hospital, Ghent, Belgium
| | - Christelle Demarquay
- 2 Institut de Radioprotection et de Sûreté Nucléaire (IRSN), Fontenay-aux-Roses, France
| | - Elke Van Daele
- 1 Department of Pediatric and Gastrointestinal Surgery, Ghent University Hospital, Ghent, Belgium
| | - Lara Moussa
- 2 Institut de Radioprotection et de Sûreté Nucléaire (IRSN), Fontenay-aux-Roses, France
| | | | - Marc Benderitter
- 2 Institut de Radioprotection et de Sûreté Nucléaire (IRSN), Fontenay-aux-Roses, France
| | - Wim Ceelen
- 1 Department of Pediatric and Gastrointestinal Surgery, Ghent University Hospital, Ghent, Belgium.,4 Cancer Research Institute Ghent (CRIG), Ghent, Belgium
| | - Piet Pattyn
- 1 Department of Pediatric and Gastrointestinal Surgery, Ghent University Hospital, Ghent, Belgium
| | - Noëlle Mathieu
- 2 Institut de Radioprotection et de Sûreté Nucléaire (IRSN), Fontenay-aux-Roses, France
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Dainiak N. Medical management of acute radiation syndrome and associated infections in a high-casualty incident. JOURNAL OF RADIATION RESEARCH 2018; 59:ii54-ii64. [PMID: 29509947 PMCID: PMC5941165 DOI: 10.1093/jrr/rry004] [Citation(s) in RCA: 53] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/05/2017] [Indexed: 05/04/2023]
Abstract
A high-casualty incident may result in a significant human toll due to the inability of a community to meet the health care demands of the population. A successful medical response requires health care facilities to not only communicate and integrate medical services, meet surge capacity, protect health care workers and implement triage and treatment protocols, but also to provide the venue for clinical management of acute radiation injuries and their associated infections. Today, clinical management is primarily guided by the recommendations of a Consultancy that were made at the World Health Organization (WHO). This international consensus was reached on evidence-based, clinical management of each of the four sub-syndromes that compose acute radiation syndrome (ARS), including the hematopoietic subsyndrome (HS), gastrointestinal subsyndrome (GIS), neurovascular subsyndrome (NVS) and cutaneous subsyndrome (CS). Major findings in studies meeting inclusion criteria for management strategies for HS were that (i) no randomized controlled studies of medical countermeasures have been (or will likely ever be) performed for ARS cases, (ii) the data for management of HS are restricted by the lack of comparator groups, and (iii) reports of countermeasures for management of injury to non-hematopoietic organs are often incompletely described. Here, (i) recommendations made in Geneva are summarized; (ii) the analysis of countermeasures for HS is updated by review of two additional cases and extended to published reports not meeting inclusion criteria; and (iii) guidelines are provided for management of microbial infections based upon patient risk for prolonged immunosuppression.
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Affiliation(s)
- Nicholas Dainiak
- Radiation Emergency Assistance Center/Training Site (REAC/TS), 1299 Bethel Valley Road, Oak Ridge, TN 37831, USA
- Department of Therapeutic Radiology, Yale University School of Medicine, LCI 202, 15 York Street, New Haven, CT 06510, USA
- Corresponding author. Tel: +1-865-576-3131; Fax: 865-576-9522;
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Yavuz E, Ercan G, Karagulle OO, Bayrak BY, Biricik A, Ercetin C, Gokcek B, Yigitbas H, Kusaslan R, Celik A, Gulcicek OB. Evaluation of prophylactic and therapeutic effects of sildenafil on acute radiation proctitis in rats. Acta Cir Bras 2018; 33:362-374. [DOI: 10.1590/s0102-865020180040000008] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2017] [Accepted: 05/20/2018] [Indexed: 01/27/2023] Open
Affiliation(s)
- Erkan Yavuz
- University of Health Science Bagcilar Training and Research Hospital, Turkey
| | - Gulcin Ercan
- University of Health Science Bagcilar Training and Research Hospital, Turkey
| | | | | | - Aytac Biricik
- University of Health Science Bagcilar Training and Research Hospital, Turkey
| | - Candas Ercetin
- University of Health Science Bagcilar Training and Research Hospital, Turkey
| | - Berk Gokcek
- University of Health Science Okmeydanı Training and Research Hospital, Turkey
| | - Hakan Yigitbas
- University of Health Science Bagcilar Training and Research Hospital, Turkey
| | - Ramazan Kusaslan
- University of Health Science Bagcilar Training and Research Hospital, Turkey
| | - Atilla Celik
- University of Health Science Bagcilar Training and Research Hospital, Turkey
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Yavuz E, Karagulle OO, Ercan G, Celik A, Yigitbas H, Bayrak BY, Tartar R, Kusaslan R, Altinel Y, Gulcicek OB. Evaluation of prophylactic and therapeutic effects of ruscogenin on acute radiation proctitis: an experimental rat model. Ann Surg Treat Res 2018; 94:174-182. [PMID: 29629351 PMCID: PMC5880974 DOI: 10.4174/astr.2018.94.4.174] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2017] [Revised: 08/22/2017] [Accepted: 08/26/2017] [Indexed: 01/27/2023] Open
Abstract
Purpose Radiation proctitis (RP) is inflammation and damage to the rectum, manifested secondary to ionizing radiation utilized for treatment. In this study, we evaluated the anti-inflammatory therapeutical and protective effects of ruscogenin in a model of acute RP. Methods Thirty-two Sprague-Dawley rats were divided into 4 groups (n = 8) as sham, control, treatment, and prophylaxis groups. Prophylaxis group and treatment group were dosed ruscogenin by oral gavage for 14 days pre- and postradiation. At the end of the 28th day, all subjects were sacrificed. Results Histopathological analysis showed a significant increase in cryptitis abscess, cryptitis and reactive atypia, and depth of lymphocytic infiltration of the control group, compared to the other groups (P < 0.05), while treatment and prophylaxis groups showed significant decreases (P < 0.05). Immunohistochemical analysis indicated that immunoreactivity were significantly higher in control group (P < 0.05, P < 0.001, and P < 0.01, respectively), but vice versa for treatment and prophylaxis groups. There was not any significant difference for fibroblast growth factor 2 immunoreactivity. The epithelium of control rectums indicated an increase in TNF-α immunoreactivity while other groups had significant decrease (P < 0.01). Electron microscopical findings were parallel to light microscopy. Conclusion In this study, ruscogenin was observed to be effective on prophylaxis or treatment of acute RP. Although there are various reports on the treatment of the rectum damaged by acute RP in the literature, this could be the first study since there is no research indicating the ultrastructural effect of ruscogenin.
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Affiliation(s)
- Erkan Yavuz
- Department of General Surgery, Istanbul Bagcilar Training and Research Hospital, Istanbul, Turkey
| | - Onur Olgac Karagulle
- Department of General Surgery, Istanbul Bagcilar Training and Research Hospital, Istanbul, Turkey
| | - Gulcin Ercan
- Department of General Surgery, Istanbul Bagcilar Training and Research Hospital, Istanbul, Turkey
| | - Atilla Celik
- Department of General Surgery, Istanbul Bagcilar Training and Research Hospital, Istanbul, Turkey
| | - Hakan Yigitbas
- Department of General Surgery, Istanbul Bagcilar Training and Research Hospital, Istanbul, Turkey
| | - Busra Yaprak Bayrak
- Department of Pathology, Kocaeli Derince Training and Research Hospital, Kocaeli, Turkey
| | - Rumeysa Tartar
- Department of General Surgery, Istanbul Bagcilar Training and Research Hospital, Istanbul, Turkey
| | - Ramazan Kusaslan
- Department of General Surgery, Istanbul Bagcilar Training and Research Hospital, Istanbul, Turkey
| | - Yuksel Altinel
- Department of General Surgery, Istanbul Bagcilar Training and Research Hospital, Istanbul, Turkey
| | - Osman Bilgin Gulcicek
- Department of General Surgery, Istanbul Bagcilar Training and Research Hospital, Istanbul, Turkey
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Khalil A, Omran H. The role of gut in type 2 diabetes mellitus during whole body gamma irradiation in high-fat diet Wistar rats. Int J Radiat Biol 2017; 94:137-149. [PMID: 29252073 DOI: 10.1080/09553002.2018.1419300] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
PURPOSE The effects of a low rate (100 mGy/min) fractionated whole body gamma irradiation (FWBGI) at different doses were assessed using a real-time PCR technique on the expression of some target genes implicated in the development of type 2 diabetes mellitus in high-fat diet (HFD) Wistar rats. METHOD HFD Wistar rats were exposed to different doses (12, 24 and 48 Gy) divided into 24 fractions (three times a week for two months), thus, the daily doses were 0.5, 1, 2 Gy, respectively. Total RNA was extracted and the expression of target genes was measured in the four intestinal segments (duodenum, jejunum, ileum and colon). RESULTS The pre-diabetic state already induced by HFD was found to be improved by irradiation exposure. This irradiation effect occurs mainly via altered anti-diabetic gene expressions (mRNA and protein levels) of the incretin glucagon-like peptide-1 (GLP-1) overall bowel segments except the colon which has its own specific response to irradiation exposure by the induction of the insulin receptor substrate 4 (IRS-4) and the uncoupling protein 3 (UCP3). CONCLUSIONS Results could be of great importance suggesting for the first time, a protective role for FWBGI on HFD animal models by increasing GLP-1 and UCP3 levels.
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Affiliation(s)
- Ayman Khalil
- a Department of Radiation Medicine, Human Nutrition Laboratory , Atomic Energy Commission of Syria (AECS) , Damascus , Syria
| | - Hasan Omran
- a Department of Radiation Medicine, Human Nutrition Laboratory , Atomic Energy Commission of Syria (AECS) , Damascus , Syria
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Abd El-Hady AM, Gewefel HS, Badawi MA, Eltahawy NA. Gamma-aminobutyric acid ameliorates gamma rays-induced oxidative stress in the small intestine of rats. THE JOURNAL OF BASIC AND APPLIED ZOOLOGY 2017; 78:2. [DOI: 10.1186/s41936-017-0005-3] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/02/2023]
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Miousse IR, Pathak R, Garg S, Skinner CM, Melnyk S, Pavliv O, Hendrickson H, Landes RD, Lumen A, Tackett AJ, Deutz NE, Hauer-Jensen M, Koturbash I. Short-term dietary methionine supplementation affects one-carbon metabolism and DNA methylation in the mouse gut and leads to altered microbiome profiles, barrier function, gene expression and histomorphology. GENES & NUTRITION 2017; 12:22. [PMID: 28904640 PMCID: PMC5588631 DOI: 10.1186/s12263-017-0576-0] [Citation(s) in RCA: 42] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/01/2017] [Accepted: 08/28/2017] [Indexed: 12/24/2022]
Abstract
BACKGROUND Methionine, a central molecule in one-carbon metabolism, is an essential amino acid required for normal growth and development. Despite its importance to biological systems, methionine is toxic when administered at supra-physiological levels. The aim of this study was to investigate the effects of short-term methionine dietary modulation on the proximal jejunum, the section of the gut specifically responsible for amino acid absorption, in a mouse model. Eight-week-old CBA/J male mice were fed methionine-adequate (MAD; 6.5 g/kg) or methionine-supplemented (MSD; 19.5 g/kg) diets for 3.5 or 6 days (average food intake 100 g/kg body weight). The study design was developed in order to address the short-term effects of the methionine supplementation that corresponds to methionine dietary intake in Western populations. Biochemical indices in the blood as well as metabolic, epigenetic, transcriptomic, metagenomic, and histomorphological parameters in the gut were evaluated. RESULTS By day 6, feeding mice with MSD (protein intake <10% different from MAD) resulted in increased plasma (2.3-fold; p < 0.054), but decreased proximal jejunum methionine concentrations (2.2-fold; p < 0.05) independently of the expression of neutral amino acid transporters. MSD has also caused small bowel bacteria colonization, increased the abundance of pathogenic bacterial species Burkholderiales and decreased the gene expression of the intestinal transmembrane proteins-Cldn8 (0.18-fold, p < 0.05), Cldn9 (0.24-fold, p < 0.01) and Cldn10 (0.05-fold, p < 0.05). Feeding MSD led to substantial histomorphological alterations in the proximal jejunum exhibited as a trend towards decreased plasma citrulline concentrations (1.8-fold, p < 0.07), as well as loss of crypt depth (by 28%, p < 0.05) and mucosal surface (by 20%, p < 0.001). CONCLUSIONS Together, these changes indicate that short-term feeding of MSD substantially alters the normal gut physiology. These effects may contribute to the pathogenesis of intestinal inflammatory diseases and/or sensitize the gut to exposure to other stressors.
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Affiliation(s)
- Isabelle R. Miousse
- Department of Environmental and Occupational Health, University of Arkansas for Medical Sciences, 4301 W. Markham Str., Slot 820-11, Little Rock, AR 72205-7199 USA
| | - Rupak Pathak
- Department of Pharmaceutical Sciences, University of Arkansas for Medical Sciences, Little Rock, AR 72205 USA
| | - Sarita Garg
- Department of Pharmaceutical Sciences, University of Arkansas for Medical Sciences, Little Rock, AR 72205 USA
| | - Charles M. Skinner
- Department of Environmental and Occupational Health, University of Arkansas for Medical Sciences, 4301 W. Markham Str., Slot 820-11, Little Rock, AR 72205-7199 USA
| | - Stepan Melnyk
- Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, AR 72205 USA
| | - Oleksandra Pavliv
- Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, AR 72205 USA
| | - Howard Hendrickson
- Department of Pharmaceutical Sciences, University of Arkansas for Medical Sciences, Little Rock, AR 72205 USA
| | - Reid D. Landes
- Department of Biostatistics, University of Arkansas for Medical Sciences, Little Rock, AR 72205 USA
| | - Annie Lumen
- Division of Biochemical Toxicology, National Center for Toxicological Research, U.S. Food and Drug Administration, Jefferson, AR USA
| | - Alan J. Tackett
- Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, AR 72205 USA
- Department of Biochemistry, University of Arkansas for Medical Sciences, Little Rock, AR USA
| | - Nicolaas E.P. Deutz
- Department of Health and Kinesiology, Center for Translational Research on Aging and Longevity, Texas A&M University, College Station, TX USA
| | - Martin Hauer-Jensen
- Department of Pharmaceutical Sciences, University of Arkansas for Medical Sciences, Little Rock, AR 72205 USA
| | - Igor Koturbash
- Department of Environmental and Occupational Health, University of Arkansas for Medical Sciences, 4301 W. Markham Str., Slot 820-11, Little Rock, AR 72205-7199 USA
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Wang J, Pathak R, Garg S, Hauer-Jensen M. Fibrinogen deficiency suppresses the development of early and delayed radiation enteropathy. World J Gastroenterol 2017; 23:4701-4711. [PMID: 28765691 PMCID: PMC5514635 DOI: 10.3748/wjg.v23.i26.4701] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/17/2016] [Revised: 06/05/2017] [Accepted: 06/19/2017] [Indexed: 02/06/2023] Open
Abstract
AIM To determine the mechanistic role of fibrinogen, a key regulator of inflammation and fibrosis, in early and delayed radiation enteropathy.
METHODS Fibrinogen wild-type (Fib+/+), fibrinogen heterozygous (Fib+/-), and fibrinogen knockout (Fib-/-) mice were exposed to localized intestinal irradiation and assessed for early and delayed structural changes in the intestinal tissue. A 5-cm segment of ileum of mice was exteriorized and exposed to 18.5 Gy of x-irradiation. Intestinal tissue injury was assessed by quantitative histology, morphometry, and immunohistochemistry at 2 wk and 26 wk after radiation. Plasma fibrinogen level was measured by enzyme-linked immunosorbent assay.
RESULTS There was no difference between sham-irradiated Fib+/+ and Fib+/- mice in terms of fibrinogen concentration in plasma and intestinal tissue, intestinal histology, morphometry, intestinal smooth muscle cell proliferation, and neutrophil infiltration. Therefore, Fib+/- mice were used as littermate controls. Unlike sham-irradiated Fib+/+ and Fib+/- mice, no fibrinogen was detected in the plasma and intestinal tissue of sham-irradiated Fib-/- mice. Moreover, fibrinogen level was not elevated after irradiation in the intestinal tissue of Fib-/- mice, while significant increase in intestinal fibrinogen level was noticed in irradiated Fib+/+ and Fib+/- mice. Importantly, irradiated Fib-/- mice exhibited substantially less overall intestinal structural injury (RIS, P = 0.000002), intestinal wall thickness (P = 0.003), intestinal serosal thickness (P = 0.009), collagen deposition (P = 0.01), TGF-β immunoreactivity (P = 0.03), intestinal smooth muscle proliferation (P = 0.046), neutrophil infiltration (P = 0.01), and intestinal mucosal injury (P = 0.0003), compared to irradiated Fib+/+ and Fib+/- mice at both 2 wk and 26 wk.
CONCLUSION These data demonstrate that fibrinogen deficiency directly attenuates development of early and delayed radiation enteropathy. Fibrinogen could be a novel target in treating intestinal damage.
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Singh VK, Hanlon BK, Santiago PT, Seed TM. A review of radiation countermeasures focusing on injury-specific medicinals and regulatory approval status: part III. Countermeasures under early stages of development along with 'standard of care' medicinal and procedures not requiring regulatory approval for use. Int J Radiat Biol 2017; 93:885-906. [PMID: 28657400 DOI: 10.1080/09553002.2017.1332440] [Citation(s) in RCA: 52] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
PURPOSE Terrorist attacks, with their intent to maximize psychological and economic damage as well as inflicting sickness and death on given targeted populations, are an ever-growing worldwide concern in government and public sectors as they become more frequent, violent, and sensational. If given the chance, it is likely that terrorists will use radiological or nuclear weapons. To thwart these sinister efforts, both physical and medical countermeasures against these weapons are currently being researched and developed so that they can be utilized by the first responders, military, and medical providers alike. This is the third article of a three-part series in which we have reviewed additional radiation countermeasures that are currently under early preclinical phases of development using largely animal models and have listed and discussed clinical support measures, including agents used for radiation-induced emesis, as well as countermeasures not requiring Food and Drug Administration approval. CONCLUSIONS Despite the significant progress that has been made in this area during the last several years, additional effort is needed in order to push promising new agents, currently under development, through the regulatory pipeline. This pipeline for new promising drugs appears to be unreasonably slow and cumbersome; possible reasons for this inefficiency are briefly discussed. Significant and continued effort needs to be afforded to this research and development area, as to date, there is no approved radioprotector that can be administered prior to high dose radiation exposure. This represents a very significant, unmet medical need and a significant security issue. A large number of agents with potential to interact with different biological targets are under development. In the next few years, several additional radiation countermeasures will likely receive Food and Drug Administration approval, increasing treatment options for victims exposed to unwanted ionizing irradiation.
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Affiliation(s)
- Vijay K Singh
- a Division of Radioprotection, Department of Pharmacology and Molecular Therapeutics , F. Edward Hébert School of Medicine, Uniformed Services University of the Health Sciences , Bethesda , MD , U.S.A.,b Armed Forces Radiobiology Research Institute , Uniformed Services University of the Health Sciences , Bethesda , MD , U.S.A
| | - Briana K Hanlon
- a Division of Radioprotection, Department of Pharmacology and Molecular Therapeutics , F. Edward Hébert School of Medicine, Uniformed Services University of the Health Sciences , Bethesda , MD , U.S.A.,b Armed Forces Radiobiology Research Institute , Uniformed Services University of the Health Sciences , Bethesda , MD , U.S.A
| | - Paola T Santiago
- a Division of Radioprotection, Department of Pharmacology and Molecular Therapeutics , F. Edward Hébert School of Medicine, Uniformed Services University of the Health Sciences , Bethesda , MD , U.S.A.,b Armed Forces Radiobiology Research Institute , Uniformed Services University of the Health Sciences , Bethesda , MD , U.S.A
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Miousse IR, Tobacyk J, Melnyk S, James SJ, Cheema AK, Boerma M, Hauer-Jensen M, Koturbash I. One-carbon metabolism and ionizing radiation: a multifaceted interaction. Biomol Concepts 2017; 8:83-92. [PMID: 28574375 PMCID: PMC6693336 DOI: 10.1515/bmc-2017-0003] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2017] [Accepted: 05/03/2017] [Indexed: 01/20/2023] Open
Abstract
Ionizing radiation (IR) is a ubiquitous component of our environment and an important tool in research and medical treatment. At the same time, IR is a potent genotoxic and epigenotoxic stressor, exposure to which may lead to negative health outcomes. While the genotoxocity is well described and characterized, the epigenetic effects of exposure to IR and their mechanisms remain under-investigated. In this conceptual review, we propose the IR-induced changes to one-carbon metabolism as prerequisites to alterations in the cellular epigenome. We also provide evidence from both experimental and clinical studies describing the interactions between IR and one-carbon metabolism. We further discuss the potential for the manipulation of the one-carbon metabolism in clinical applications for the purpose of normal tissue protection and for increasing the radiosensitivity of cancerous cells.
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Affiliation(s)
- Isabelle R. Miousse
- Department of Environmental and Occupational Health, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA
| | - Julia Tobacyk
- Departments of Environmental and Occupational Health, and Pharmacology and Toxicology, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA
| | - Stepan Melnyk
- Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA
| | - S. Jill James
- Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA
| | - Amrita K. Cheema
- Departments of Oncology and Biochemistry, Molecular and Cellular Biology, Georgetown University Medical Center, Washington DC 20057, USA
| | - Marjan Boerma
- Division of Radiation Health, Department of Pharmaceutical Sciences, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA
| | - Martin Hauer-Jensen
- Division of Radiation Health, Department of Pharmaceutical Sciences, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA
| | - Igor Koturbash
- Department of Environmental and Occupational Health, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA
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Molecular Contrast-Enhanced Ultrasound Imaging of Radiation-Induced P-Selectin Expression in Healthy Mice Colon. Int J Radiat Oncol Biol Phys 2017; 97:581-585. [DOI: 10.1016/j.ijrobp.2016.10.037] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2016] [Revised: 09/14/2016] [Accepted: 10/23/2016] [Indexed: 12/30/2022]
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Jensen MM, Jia W, Isaacson KJ, Schults A, Cappello J, Prestwich GD, Oottamasathien S, Ghandehari H. Silk-elastinlike protein polymers enhance the efficacy of a therapeutic glycosaminoglycan for prophylactic treatment of radiation-induced proctitis. J Control Release 2017; 263:46-56. [PMID: 28232224 DOI: 10.1016/j.jconrel.2017.02.025] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2016] [Revised: 02/15/2017] [Accepted: 02/19/2017] [Indexed: 12/17/2022]
Abstract
Radiation-induced proctitis (RIP) is the most common clinical adverse effect for patients receiving radiotherapy as part of the standard course of treatment for ovarian, prostate, colon, and bladder cancers. RIP limits radiation dosage, interrupts treatment, and lowers patients' quality of life. A prophylactic treatment that protects the gastrointestinal tract from deleterious effects of radiotherapy will significantly improve patient quality of life and may allow for higher and more regular doses of radiation therapy. Semi-synthetic glycosaminoglycan (GAG), generated from the sulfation of hyaluronic acid, are anti-inflammatory but have difficulty achieving therapeutic levels in many tissues. To enhance the delivery of GAG, we created an in situ gelling rectal delivery system using silk-elastinlike protein polymers (SELPs). Using solutions of SELP 815K (which contains 6 repeats of blocks comprised of 8 silk-like units, 15 elastin-like units, and 1 lysine-substituted elastin-like unit) with GAG GM-0111, we created an injectable delivery platform that transitioned in <5min from a liquid at room temperature to a hydrogel at body temperature. The hydrogels released 50% of their payload within 30min and enhanced the accumulation of GAG in the rectum compared to traditional enema-based delivery. Using a murine model of radiation-induced proctitis, the prophylactic delivery of a single dose of GAG from a SELP matrix administered prior to irradiation significantly reduced radiation-induced pain after 3, 7, and 21days by 53±4%, 47±10%, and 12±6%, respectively. Matrix-mediated delivery of GAG by SELP represents an innovative method for more effective treatment of RIP and promises to improve quality of life of cancer patients by allowing higher radiotherapy doses with improved safety.
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Affiliation(s)
- Mark Martin Jensen
- Department of Bioengineering, University of Utah, Salt Lake City, UT 84112, USA; Utah Center for Nanomedicine, Nano Institute of Utah, University of Utah, Salt Lake City, UT 84112, USA
| | - Wanjian Jia
- Division of Urology, Section of Pediatric Urology, University of Utah, Salt Lake City, UT 84113, USA
| | - Kyle J Isaacson
- Department of Bioengineering, University of Utah, Salt Lake City, UT 84112, USA; Utah Center for Nanomedicine, Nano Institute of Utah, University of Utah, Salt Lake City, UT 84112, USA
| | - Austin Schults
- Division of Urology, Section of Pediatric Urology, University of Utah, Salt Lake City, UT 84113, USA
| | - Joseph Cappello
- Department of Pharmaceutics and Pharmaceutical Chemistry, University of Utah, Salt Lake City, UT 84112, USA
| | - Glenn D Prestwich
- Department of Medicinal Chemistry, University of Utah, Salt Lake City, UT 84112, USA
| | - Siam Oottamasathien
- Division of Urology, Section of Pediatric Urology, University of Utah, Salt Lake City, UT 84113, USA; Department of Surgery and Division of Pediatric Urology, Primary Children's Hospital, Salt Lake City, UT 84113, USA.
| | - Hamidreza Ghandehari
- Department of Bioengineering, University of Utah, Salt Lake City, UT 84112, USA; Utah Center for Nanomedicine, Nano Institute of Utah, University of Utah, Salt Lake City, UT 84112, USA; Department of Pharmaceutics and Pharmaceutical Chemistry, University of Utah, Salt Lake City, UT 84112, USA.
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Strup-Perrot C, Vozenin MC, Monceau V, Pouzoulet F, Petit B, Holler V, Perrot S, Desquibert L, Fouquet S, Souquere S, Pierron G, Rousset M, Thenet S, Cardot P, Benderitter M, Deutsch E, Aigueperse J. PrP(c) deficiency and dasatinib protect mouse intestines against radiation injury by inhibiting of c-Src. Radiother Oncol 2016; 120:175-83. [PMID: 27406443 DOI: 10.1016/j.radonc.2016.06.009] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2013] [Revised: 04/13/2016] [Accepted: 06/14/2016] [Indexed: 10/21/2022]
Abstract
BACKGROUND & AIM Despite extensive study of the contribution of cell death and apoptosis to radiation-induced acute intestinal injury, our knowledge of the signaling mechanisms involved in epithelial barrier dysfunction remains inadequate. Because PrP(c) plays a key role in intestinal homeostasis by renewing epithelia, we sought to study its role in epithelial barrier function after irradiation. DESIGN Histology, morphometry and plasma FD-4 levels were used to examine ileal architecture, wound healing, and intestinal leakage in PrP(c)-deficient (KO) and wild-type (WT) mice after total-body irradiation. Impairment of the PrP(c) Src pathway after irradiation was explored by immunofluorescence and confocal microscopy, with Caco-2/Tc7 cells. Lastly, dasatinib treatment was used to switch off the Src pathway in vitro and in vivo. RESULTS The decrease in radiation-induced lethality, improved intestinal wound healing, and reduced intestinal leakage promoted by PrP(c) deficiency demonstrate its involvement in acute intestinal damage. Irradiation of Cacao2/Tc7 cells induced PrP(c) to target the nuclei associated with Src activation. Finally, the protective effect triggered by dasatinib confirmed Src involvement in radiation-induced acute intestinal toxicity. CONCLUSION Our data are the first to show a role for the PrP(c)-Src pathway in acute intestinal response to radiation injury and offer a novel therapeutic opportunity.
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Affiliation(s)
- Carine Strup-Perrot
- Institut de Radioprotection et de Sûreté Nucléaire, PRP-HOM, SRBE, Laboratoire de Recherche sur la Régénération des tissus sains Irradiés, Fontenay-aux-Roses, France
| | - Marie-Catherine Vozenin
- Inserm U1030, Radiotherapie experimentale, Institut Gustave Roussy, Villejuif, France; Laboratoire de Radio-Oncologie, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland
| | - Virginie Monceau
- Institut de Radioprotection et de Sûreté Nucléaire, PRP-HOM, SRBE, Laboratoire de Recherche sur la Régénération des tissus sains Irradiés, Fontenay-aux-Roses, France; Inserm U1030, Radiotherapie experimentale, Institut Gustave Roussy, Villejuif, France
| | - Frederic Pouzoulet
- Institut Curie, Translational Research Department, Hopital St Louis, Paris, France
| | - Benoit Petit
- Laboratoire de Radio-Oncologie, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland; Service Commun d'Expérimentation Animale, Institut Gustave Roussy, Villejuif, France
| | - Valérie Holler
- Institut de Radioprotection et de Sûreté Nucléaire, PRP-HOM, SRBE, Laboratoire de Recherche sur la Régénération des tissus sains Irradiés, Fontenay-aux-Roses, France
| | - Sébastien Perrot
- Université Paris-Est, Ecole Nationale Vétérinaire d'Alfort, Institut de Recherche Clinique Animale, Maisons-Alfort Cedex, France
| | - Loïc Desquibert
- Université Paris-Est, Ecole Nationale Vétérinaire d'Alfort, Institut de Recherche Clinique Animale, Maisons-Alfort Cedex, France
| | - Stéphane Fouquet
- Stéphane FOUQUET, Centre de Recherche Institut de la Vision, UMR_S968 Inserm/UPMC/CHNO des Quinze-Vingts, Paris, France
| | | | - Gérard Pierron
- CNRS, UMR-8122, Institut Gustave Roussy, Villejuif, France
| | - Monique Rousset
- Centre de Recherche des Cordeliers, Université Pierre et Marie Curie-Paris 6, UMR S 872, France; INSERM, U 872, Paris, France; Université Paris Descartes-Paris 5, UMR S 872, France
| | - Sophie Thenet
- Centre de Recherche des Cordeliers, Université Pierre et Marie Curie-Paris 6, UMR S 872, France; INSERM, U 872, Paris, France; Université Paris Descartes-Paris 5, UMR S 872, France; Ecole Pratique des Hautes Etudes, Laboratoire de Pharmacologie Cellulaire et Moléculaire, Paris, France
| | - Philippe Cardot
- Centre de Recherche des Cordeliers, Université Pierre et Marie Curie-Paris 6, UMR S 872, France; INSERM, U 872, Paris, France; Université Paris Descartes-Paris 5, UMR S 872, France
| | - Marc Benderitter
- Institut de Radioprotection et de Sûreté Nucléaire, PRP-HOM, SRBE, Laboratoire de Recherche sur la Régénération des tissus sains Irradiés, Fontenay-aux-Roses, France
| | - Eric Deutsch
- Inserm U1030, Radiotherapie experimentale, Institut Gustave Roussy, Villejuif, France
| | - Jocelyne Aigueperse
- Institut de Radioprotection et de Sûreté Nucléaire, PRP-HOM, Fontenay-aux-Roses, France
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Protection against Radiotherapy-Induced Toxicity. Antioxidants (Basel) 2016; 5:antiox5030022. [PMID: 27399787 PMCID: PMC5039571 DOI: 10.3390/antiox5030022] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2016] [Revised: 06/27/2016] [Accepted: 06/28/2016] [Indexed: 01/18/2023] Open
Abstract
Radiation therapy is a highly utilized therapy in the treatment of malignancies with up to 60% of cancer patients receiving radiation therapy as a part of their treatment regimen. Radiation therapy does, however, cause a wide range of adverse effects that can be severe and cause permanent damage to the patient. In an attempt to minimize these effects, a small number of compounds have been identified and are in use clinically for the prevention and treatment of radiation associated toxicities. Furthermore, there are a number of emerging therapies being developed for use as agents that protect against radiation-induced toxicities. The aim of this review was to evaluate and summarise the evidence that exists for both the known radioprotectant agents and the agents that show promise as future radioprotectant agents.
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Advances in understanding and improving gastrointestinal symptoms during supportive and palliative care: a decade of progress. Curr Opin Support Palliat Care 2016; 10:149-51. [PMID: 27054289 DOI: 10.1097/spc.0000000000000215] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
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Tas S, Ozkul F, Arik MK, Kiraz A, Vural A. The effect of amifostine on bacterial translocation after radiation ınduced acute enteritis. Acta Cir Bras 2016; 31:156-60. [DOI: 10.1590/s0102-865020160030000002] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2015] [Accepted: 02/15/2016] [Indexed: 11/22/2022] Open
Affiliation(s)
- Sukru Tas
- Çanakkale Onsekiz Mart University, Turkey
| | | | | | - Asli Kiraz
- Çanakkale Onsekiz Mart University, Turkey
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Zheng J, Wang J, Pouliot M, Authier S, Zhou D, Loose DS, Hauer-Jensen M. Gene expression profiling in non-human primate jejunum, ileum and colon after total-body irradiation: a comparative study of segment-specific molecular and cellular responses. BMC Genomics 2015; 16:984. [PMID: 26589571 PMCID: PMC4654820 DOI: 10.1186/s12864-015-2168-y] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2015] [Accepted: 10/29/2015] [Indexed: 12/26/2022] Open
Abstract
Background Although extensive studies have investigated radiation-induced injuries in particular gastrointestinal (GI) segments, a systematic comparison among the different segments on the basis of mode, magnitude and mechanism has not been reported. Here, a comparative study of segment-specific molecular and cellular responses was performed on jejunum, ileum and colon obtained at three time points (4, 7 and 12 days after irradiation) from non-human primate (Rhesus macaque) models exposed to 6.7 Gy or 7.4 Gy total body irradiation (TBI). Results Pathway analysis on the gene expression profiles identified radiation-induced time-, dose- and segment-dependent activation of tumor necrosis factor α (TNFα) cascade, tight junction, apoptosis, cell cycle control/DNA damage repair and coagulation system signaling. Activation of these signaling pathways suggests that colon sustained the severest mucosal barrier disruption and inflammation, and jejunum the greatest DNA damage, apoptosis and endothelial dysfunction. These more pronounced alterations correlate with the high incidence of macroscopic pathologies that are observed in the colon after TBI. Compared to colon and jejunum, ileum was resistant to radiation injury. In addition to the identification a marked increase of TNFα cascade, this study also identified radiation induced strikingly up-regulated tight junction gene CLDN2 (196-fold after 7.4-Gy TBI), matrix degradation genes such as MMP7 (increased 11- and 41-fold after 6.7-Gy and 7.4-Gy TBI), and anoikis mediated gene EDA2R that mediate mucosal shedding and barrier disruption. Conclusions This is the first systematic comparative study of the molecular and cellular responses to radiation injury in jejunum, ileum and colon. The strongest activation of TNFα cascades and the striking up-regulation of its down-stream matrix-dissociated genes suggest that TNFα modulation could be a target for mitigating radiation-induced mucosal barrier disruption. Electronic supplementary material The online version of this article (doi:10.1186/s12864-015-2168-y) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Junying Zheng
- Division of Radiation Health, University of Arkansas for Medical Sciences, Little Rock, Arkansas, 72205, USA.
| | - Junru Wang
- Division of Radiation Health, University of Arkansas for Medical Sciences, Little Rock, Arkansas, 72205, USA.
| | | | - Simon Authier
- CiToxLAB North America, Laval, Quebec, Canada, H7V 4B3.
| | - Daohong Zhou
- Division of Radiation Health, University of Arkansas for Medical Sciences, Little Rock, Arkansas, 72205, USA.
| | - David S Loose
- Integrative Biology and Pharmacology, University of Texas Medical School at Houston, Houston, TX, 77030, USA.
| | - Martin Hauer-Jensen
- Division of Radiation Health, University of Arkansas for Medical Sciences, Little Rock, Arkansas, 72205, USA. .,Surgical Service, Central Arkansas Veterans Healthcare System, Little Rock, Arkansas, 72205, USA.
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