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Martin Hauer-jensen - One of the best experts on this subject based on the ideXlab platform.
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Pharmacological Induction of Transforming Growth Factor-Beta1 in Rat Models Enhances Radiation Injury in the Intestine and the Heart
2016Co-Authors: Marjan Boerma, Junru Wang, Jean-marc Herbert, Vijayalakshmi Sridharan, Martin Hauer-jensenAbstract:Radiation therapy in the treatment of cancer is dose limited by Radiation Injury in normal tissues such as the intestine and the heart. To identify the mechanistic involvement of transforming growth factor-beta 1 (TGF-b1) in intestinal and cardiac Radiation Injury, we studied the influence of pharmacological induction of TGF-b1 with xaliproden (SR 57746A) in rat models of Radiation enteropathy and Radiation-induced heart disease (RIHD). Because it was uncertain to what extent TGF-b induction may enhance Radiation Injury in heart and intestine, animals were exposed to irRadiation schedules that cause mild to moderate (acute) Radiation Injury. In the Radiation enteropathy model, male Sprague-Dawley rats received local irRadiation of a 4-cm loop of rat ileum with 7 once-daily fractions of 5.6 Gy, and intestinal Injury was assessed at 2 weeks and 12 weeks after irRadiation. In the RIHD model, male Sprague-Dawley rats received local heart irRadiation with a single dose of 18 Gy and were followed for 6 months after irRadiation. Rats were treated orally with xaliproden starting 3 days before irRadiation until the end of the experiments. Treatment with xaliproden increased circulating TGF-b1 levels by 300 % and significantly induced expression of TGF-b1 and TGF-b1 target genes in the irradiated intestine and heart. Various Radiation-induced structural changes in the intestine at 2 and 12 weeks were significantly enhanced with TGF-b1 induction. Similarly, in the RIHD model induction of TGF-b1 augmented Radiation-induced changes in cardiac function and myocardial fibrosis. These results lend further support for the direct involvement of TGF-b1 in biological mechanisms of Radiation-induce
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Pharmacological Induction of Transforming Growth Factor-Beta1 in Rat Models Enhances Radiation Injury in the Intestine and the Heart
PloS one, 2013Co-Authors: Marjan Boerma, Junru Wang, Jean-marc Herbert, Vijayalakshmi Sridharan, Martin Hauer-jensenAbstract:Radiation therapy in the treatment of cancer is dose limited by Radiation Injury in normal tissues such as the intestine and the heart. To identify the mechanistic involvement of transforming growth factor-beta 1 (TGF-β1) in intestinal and cardiac Radiation Injury, we studied the influence of pharmacological induction of TGF-β1 with xaliproden (SR 57746A) in rat models of Radiation enteropathy and Radiation-induced heart disease (RIHD). Because it was uncertain to what extent TGF-β induction may enhance Radiation Injury in heart and intestine, animals were exposed to irRadiation schedules that cause mild to moderate (acute) Radiation Injury. In the Radiation enteropathy model, male Sprague-Dawley rats received local irRadiation of a 4-cm loop of rat ileum with 7 once-daily fractions of 5.6 Gy, and intestinal Injury was assessed at 2 weeks and 12 weeks after irRadiation. In the RIHD model, male Sprague-Dawley rats received local heart irRadiation with a single dose of 18 Gy and were followed for 6 months after irRadiation. Rats were treated orally with xaliproden starting 3 days before irRadiation until the end of the experiments. Treatment with xaliproden increased circulating TGF-β1 levels by 300% and significantly induced expression of TGF-β1 and TGF-β1 target genes in the irradiated intestine and heart. Various Radiation-induced structural changes in the intestine at 2 and 12 weeks were significantly enhanced with TGF-β1 induction. Similarly, in the RIHD model induction of TGF-β1 augmented Radiation-induced changes in cardiac function and myocardial fibrosis. These results lend further support for the direct involvement of TGF-β1 in biological mechanisms of Radiation-induced adverse remodeling in the intestine and the heart.
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Activation of Protease Activated Receptor 2 by Exogenous Agonist Exacerbates Early Radiation Injury in Rat Intestine
International journal of radiation oncology biology physics, 2010Co-Authors: Junru Wang, Marjan Boerma, Ashwini Kulkarni, Morley D. Hollenberg, Martin Hauer-jensenAbstract:Purpose Protease-activated receptor-2 (PAR 2 ) is highly expressed throughout the gut and regulates the inflammatory, mitogenic, fibroproliferative, and nociceptive responses to Injury. PAR 2 is strikingly upregulated and exhibits increased activation in response to intestinal irRadiation. We examined the mechanistic significance of Radiation enteropathy development by assessing the effect of exogenous PAR 2 activation. Methods and Materials Rat small bowel was exposed to localized single-dose Radiation (16.5 Gy). The PAR 2 agonist (2-furoyl-LIGRLO-NH 2 ) or vehicle was injected intraperitoneally daily for 3 days before irRadiation (before), for 7 days after irRadiation (after), or both 3 days before and 7 days after irRadiation (before-after). Early and delayed Radiation enteropathy was assessed at 2 and 26 weeks after irRadiation using quantitative histologic examination, morphometry, and immunohistochemical analysis. Results The PAR 2 agonist did not elicit changes in the unirradiated (shielded) intestine. In contrast, in the irradiated intestine procured 2 weeks after irRadiation, administration of the PAR 2 agonist was associated with more severe mucosal Injury and increased intestinal wall thickness in all three treatment groups ( p 2 agonist also exacerbated the Radiation Injury score, serosal thickening, and mucosal inflammation ( p 2 did not affect Radiation-induced intestinal Injury at 26 weeks. Conclusion The results of the present study support a role for PAR 2 activation in the pathogenesis of early Radiation-induced intestinal Injury. Pharmacologic PAR 2 antagonists might have the potential to reduce the intestinal side effects of radiotherapy and/or as countermeasures in radiologic accidents or terrorism scenarios.
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Up-regulation and Activation of Proteinase-Activated Receptor 2 in Early and Delayed Radiation Injury in the Rat Intestine: Influence of Biological Activators of Proteinase-Activated Receptor 2
Radiation research, 2003Co-Authors: Junru Wang, Morley D. Hollenberg, Huaien Zheng, Suranga J. Wijesuriya, Martin Hauer-jensenAbstract:Abstract Wang, J., Zheng, H., Hollenberg, M. D., Wijesuriya, S. J., Ou, X. and Hauer-Jensen, M. Up-regulation and Activation of Proteinase-Activated Receptor 2 in Early and Delayed Radiation Injury in the Rat Intestine: Influence of Biological Activators of Proteinase-Activated Receptor 2. Radiat. Res. 160, 524–535 (2003). Proteinase-activated receptor 2 (Par2, F2rl1, also designated PAR-2 or PAR2) is prominently expressed in the intestine and has been suggested as a mediator of inflammatory, mitogenic and fibrogenic responses to Injury. Mast cell proteinases and pancreatic trypsin, both of which have been shown to affect the intestinal Radiation response, are the major biological activators of Par2. Conventional Sprague-Dawley rats, mast cell-deficient rats, and rats in which pancreatic exocrine secretion was blocked pharmacologically by octreotide underwent localized irRadiation of a 4-cm loop of small bowel. Radiation Injury was assessed 2 weeks after irRadiation (early, inflammatory phase) and 26 week...
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Role of mast cells in early and delayed Radiation Injury in rat intestine.
Radiation Research, 2000Co-Authors: Huaien Zheng, Junru Wang, Martin Hauer-jensenAbstract:Abstract Zheng, H., Wang, J. and Hauer-Jensen, M. Role of Mast Cells in Early and Delayed Radiation Injury in Rat Intestine. Mast cell hyperplasia is a characteristic feature of many inflammatory and fibrotic conditions, including intestinal Radiation Injury (Radiation enteropathy). This study used mast cell-deficient rats to define the role of mast cells in the mechanisms underlying early Radiation-induced mucosal Injury and delayed intestinal wall fibrosis. Mast cell-deficient (Ws/Ws) mutant rats and mast cell-competent (+/+) littermates were used. A 4-cm loop of ileum was exposed to 21 Gy single-dose Radiation. Irradiated and unirradiated intestine were examined at 2 or 26 weeks using quantitative histology and morphometry. Quantitative immunohistochemistry was used to assess transforming growth factor β (Tgfb), myeloperoxidase, and epithelial and smooth muscle cell proliferation. Collagen content was measured colorimetrically, and steady-state Tgfb1 mRNA was determined with fluorogenic probe RT-PCR. C...
P C Sundgren - One of the best experts on this subject based on the ideXlab platform.
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MR Spectroscopy in Radiation Injury
2020Co-Authors: P C SundgrenAbstract:SUMMARY: Detecting a new area of contrast enhancement in or in the vicinity of a previously treated brain tumor always causes concern for both the patient and the physician. The question that immediately arises is whether this new lesion is recurrent tumor or a treatment effect. The differentiation of recurrent tumor or progressive tumor from Radiation Injury after Radiation therapy is often a radiologic dilemma regardless the technique used, CT or MR imaging. The purpose of this article was to review the utility of one of the newer MR imaging techniques, MR spectroscopy, to distinguish recurrent tumor from Radiation necrosis or Radiation Injury. N ew contrast enhancing lesions discovered on routine follow-up brain imaging at or near the site of previously treated primary brain tumor present a diagnostic dilemma. Posttreatment imaging features are often non-specific and the differentiation between recurrent tumor and Radiation Injury is often difficult. In attempts by investigators to improve local tumor control and the overall clinical outcome and survival for patients with primary brain tumor, new, more aggressive treatment protocols are implemented or tested. These protocols include different schemes of dosages of various chemotherapeutic agents but also different schemes of locally administered high doses of Radiation. Although these new Radiation schemes have resulted in improved outcome, they have also been associated with a significant incidence of Radiation Injury to the brain. It is well documented that there is a relationship between increased survival and increased total dose. 2 The differentiation of recurrent tumor or progressive tumor from Radiation Injury after Radiation therapy is often a radiologic dilemma, regardless of the technique used, CT or MR imaging. Most of these brain neoplasms have been subjected to Radiation and/or chemotherapy, and many of the tumors do not have specific imaging characteristics that will enable the neuroradiologist to discriminate tumor recurrence from the inflammatory or necrotic change that can result from treatment with Radiation and/or chemotherapy. Both entities typically demonstrate contrast enhancement. It is, therefore, often the clinical course, a brain biopsy, or imaging over a lengthy follow-up interval that enables the distinction of recurrent tumor from a treatment-related lesion, not the specific imaging itself. 3 A noninvasive tool that could differentiate these entities when a new enhancing lesion is first identified would be invaluable. MR spectroscopy might be well suited for this purpose, provided that spectra of diagnostic quality can be obtained. This noninvasive imaging can be performed by using different techniques, depending on clinical question and localization of the lesion. Spectra can be acquired by using single-voxel spectroscopy (SVS) or multivoxel spectroscopy, also referred as chemical shift imaging (CSI), with both 2D CSI and, lately, 3D CSI acquisitions. Both SVS and multivoxel techniques have lately been used in the evaluation of contrastenhancing brain lesions in patients previously treated for brain neoplasms. The decision of which sequences (SVS versus 2D CSI or 3D CSI) and which parameters (ie, TE and TR) to use depends on the location of the lesion and the choice of the brain metabolites the investigator wants to evaluate. Other Radiologic and Nuclear Medicine Methods to Discriminate Radiation Injury from Recurrent or Progressive Tumor MR spectroscopy is not the only method used to differentiate Radiation Injury from recurrent tumor. Other methods that recently have been used for this purpose but that will not be discussed in detail here are positron-emission tomography (PET), diffusion-weighted imaging (DWI), MR perfusion, and CT perfusion. 4-9 Some of these techniques seem to have a lower yield than others and have demonstrated lower sensitivity and specificity than MR spectroscopy, whereas some of them seem very promising. Previous PET studies have shown that areas of Radiation Injury have lower glucose metabolism than normal brain tissue because they have lower cellular attenuation. 10 A previous PET review reported the sensitivity of PET to be 80%-90% and the specificity to be 50%-90% in differentiating late-delayed Radiation Injury from recurrent high-grade glioma. 11 Recent studies using DWI 6 have shown that the apparent diffusion coefficient (ADC) ratios in the contrast-enhancing lesion are lower in recurrent tumor than in Radiation-induced Injury 6 ; however, other investigators using diffusion tensor imaging (DTI) 7 have demonstrated higher ADC values in the contrast-enhancing part of the lesion in patients with tumor recurrence than in the contrast-enhancing lesion in patients with Radiation Injury. That study also showed that the ADC ratios in the white matter tracts in the perilesional edema were significantly higher in patients with Radiation Injury compare
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mr spectroscopy in Radiation Injury
American Journal of Neuroradiology, 2009Co-Authors: P C SundgrenAbstract:SUMMARY: Detecting a new area of contrast enhancement in or in the vicinity of a previously treated brain tumor always causes concern for both the patient and the physician. The question that immediately arises is whether this new lesion is recurrent tumor or a treatment effect. The differentiation of recurrent tumor or progressive tumor from Radiation Injury after Radiation therapy is often a radiologic dilemma regardless the technique used, CT or MR imaging. The purpose of this article was to review the utility of one of the newer MR imaging techniques, MR spectroscopy, to distinguish recurrent tumor from Radiation necrosis or Radiation Injury.
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differentiation of recurrent brain tumor versus Radiation Injury using diffusion tensor imaging in patients with new contrast enhancing lesions
Magnetic Resonance Imaging, 2006Co-Authors: P C Sundgren, Patrick Weybright, Robert C Welsh, Ruth C Carlos, Myria Petrou, Paul E Mckeever, Thomas L ChenevertAbstract:Abstract Background and Purpose The purpose of this study was to assess the use of diffusion tensor imaging (DTI) in the evaluation of new contrast-enhancing lesions and perilesional edema in patients previously treated for brain neoplasm in the differentiation of recurrent neoplasm from treatment-related Injury. Methods Twenty-eight patients with new contrast-enhancing lesions and perilesional edema at the site of previously treated brain neoplasms were retrospectively reviewed. Nine directional echoplanar DTIs with b =1000 s/mm 2 were obtained using a single-shot spin-echo echoplanar imaging. Standardized regions of interest were manually drawn in several regions. Mean apparent diffusion coefficient (ADC), fractional anisotropy (FA) and eigenvalue indices ( λ ∥ and λ ⊥ ) and their ratios relative to the contralateral side were compared in patients with recurrent neoplasm versus patients with Radiation Injury, as established by histological examination or by clinical course, including long-term imaging studies and magnetic resonance spectroscopy. Results The ADC values in the contrast-enhancing lesions were significantly higher ( P =.01) for the recurrence group (range=1.01×10 −3 to 1.66×10 −3 mm 2 /s; mean±S.D.=1.27±0.15) than for the nonrecurrence group (range=0.9×10 −3 to 1.31×10 −3 mm 2 /s; mean±S.D.=1.12±0.14). The ADC ratios in the white matter tracts in perilesional edema trended higher ( P =.09) in treatment-related Injury than in recurrent neoplasm (mean±S.D.=1.85±0.30 vs. 1.60±0.27, respectively). FA ratios were significantly higher in normal-appearing white matter (NAWM) tracts adjacent to the edema in the nonrecurrence group (mean±S.D.=0.89±0.15) than in those in the recurrence group (mean±S.D.=0.74±0.14; P =.03). Both eigenvalue indices λ ∥ and λ ⊥ were significantly higher in contrast-enhancing lesions in the recurrence group than in those in the nonrecurrence group ( P =.02). As well, both eigenvalue indices λ ∥ and λ ⊥ were significantly higher in perilesional edema than in normal white matter ( P P Conclusion The assessment of diffusion properties, especially ADC values and ADC ratios, in contrast-enhancing lesions, perilesional edema and NAWM adjacent to the edema in the follow-up of new contrast-enhancing lesions at the site of previously treated brain neoplasms may add to the information obtained by other imaging techniques in the differentiation of Radiation Injury from tumor recurrence.
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differentiation between brain tumor recurrence and Radiation Injury using mr spectroscopy
American Journal of Roentgenology, 2005Co-Authors: Patrick Weybright, P C Sundgren, Pavel Maly, Diana Gomez Hassan, S Rohrer, Larry JunckAbstract:OBJECTIVE. The purpose of our study was to explore the feasibility and utility of 2D chemical shift imaging (CSI) MR spectroscopy in the evaluation of new areas of contrast enhancement at the site of a previously treated brain neoplasm.MATERIALS AND METHODS. Two-dimensional CSI (point-resolved spectroscopy sequence [PRESS]; TR/TE, 1,500/144) was performed in 29 consecutive patients (4-54 years old; mean age, 34 years) who had a new contrast-enhancing lesion in the vicinity of a previously diagnosed and treated brain neoplasm. Clinical and imaging follow-up, and histopathology in 16 patients, were used as indicators of the identity of a lesion.RESULTS. Diagnostic-quality spectra were obtained in 97% of the patients. The Cho/Cr (choline/creatine) and Cho/NAA (choline/N-acetyl aspartate) ratios were significantly higher, and the NAA/Cr ratios significantly lower, in tumor than in Radiation Injury (all three differences, p < 0.0001). The Cho/Cr and Cho/NAA ratios were significantly higher in Radiation Injury ...
Philipp Lohmann - One of the best experts on this subject based on the ideXlab platform.
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combined fet pet mri radiomics differentiates Radiation Injury from recurrent brain metastasis
NeuroImage: Clinical, 2018Co-Authors: Gabriele Stoffels, Maximilian I Ruge, Philipp Lohmann, Martin Kocher, Garry Ceccon, Elena K Bauer, Shivakumar Viswanathan, Bernd Neumaier, Nadim Joni ShahAbstract:Abstract Background The aim of this study was to investigate the potential of combined textural feature analysis of contrast-enhanced MRI (CE-MRI) and static O-(2-[18F]fluoroethyl)-L-tyrosine (FET) PET for the differentiation between local recurrent brain metastasis and Radiation Injury since CE-MRI often remains inconclusive. Methods Fifty-two patients with new or progressive contrast-enhancing brain lesions on MRI after radiotherapy (predominantly stereotactic radiosurgery) of brain metastases were additionally investigated using FET PET. Based on histology (n = 19) or clinicoradiological follow-up (n = 33), local recurrent brain metastases were diagnosed in 21 patients (40%) and Radiation Injury in 31 patients (60%). Forty-two textural features were calculated on both unfiltered and filtered CE-MRI and summed FET PET images (20–40 min p.i.), using the software LIFEx. After feature selection, logistic regression models using a maximum of five features to avoid overfitting were calculated for each imaging modality separately and for the combined FET PET/MRI features. The resulting models were validated using cross-validation. Diagnostic accuracies were calculated for each imaging modality separately as well as for the combined model. Results For the differentiation between Radiation Injury and recurrence of brain metastasis, textural features extracted from CE-MRI had a diagnostic accuracy of 81% (sensitivity, 67%; specificity, 90%). FET PET textural features revealed a slightly higher diagnostic accuracy of 83% (sensitivity, 88%; specificity, 75%). However, the highest diagnostic accuracy was obtained when combining CE-MRI and FET PET features (accuracy, 89%; sensitivity, 85%; specificity, 96%). Conclusions Our findings suggest that combined FET PET/CE-MRI radiomics using textural feature analysis offers a great potential to contribute significantly to the management of patients with brain metastases.
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Radiation Injury vs recurrent brain metastasis combining textural feature radiomics analysis and standard parameters may increase 18 f fet pet accuracy without dynamic scans
European Radiology, 2017Co-Authors: Philipp Lohmann, Gabriele Stoffels, Christian Filss, Garry Ceccon, Marion Rapp, Michael Sabel, Marcel A Kamp, Carina Stegmayr, Bernd NeumaierAbstract:We investigated the potential of textural feature analysis of O-(2-[18F]fluoroethyl)-L-tyrosine (18F-FET) PET to differentiate Radiation Injury from brain metastasis recurrence. Forty-seven patients with contrast-enhancing brain lesions (n = 54) on MRI after radiotherapy of brain metastases underwent dynamic 18F-FET PET. Tumour-to-brain ratios (TBRs) of 18F-FET uptake and 62 textural parameters were determined on summed images 20-40 min post-injection. Tracer uptake kinetics, i.e., time-to-peak (TTP) and patterns of time-activity curves (TAC) were evaluated on dynamic PET data from 0-50 min post-injection. Diagnostic accuracy of investigated parameters and combinations thereof to discriminate between brain metastasis recurrence and Radiation Injury was compared. Diagnostic accuracy increased from 81 % for TBRmean alone to 85 % when combined with the textural parameter Coarseness or Short-zone emphasis. The accuracy of TBRmax alone was 83 % and increased to 85 % after combination with the textural parameters Coarseness, Short-zone emphasis, or Correlation. Analysis of TACs resulted in an accuracy of 70 % for kinetic pattern alone and increased to 83 % when combined with TBRmax. Textural feature analysis in combination with TBRs may have the potential to increase diagnostic accuracy for discrimination between brain metastasis recurrence and Radiation Injury, without the need for dynamic 18F-FET PET scans. • Textural feature analysis provides quantitative information about tumour heterogeneity • Textural features help improve discrimination between brain metastasis recurrence and Radiation Injury • Textural features might be helpful to further understand tumour heterogeneity • Analysis does not require a more time consuming dynamic PET acquisition
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dynamic o 2 18f fluoroethyl l tyrosine positron emission tomography differentiates brain metastasis recurrence from Radiation Injury after radiotherapy
Neuro-oncology, 2016Co-Authors: Garry Ceccon, Gabriele Stoffels, Christian Filss, Maximilian I Ruge, Philipp Lohmann, Elena K Bauer, Natalie Judov, Marion Rapp, Christina Hamisch, Martin KocherAbstract:BACKGROUND: The aim of this study was to investigate the potential of dynamic O-(2-[(18)F]fluoroethyl)-L-tyrosine ((18)F-FET) PET for differentiating local recurrent brain metastasis from Radiation Injury after radiotherapy since contrast-enhanced MRI often remains inconclusive. METHODS: Sixty-two patients (mean age, 55 ± 11 y) with single or multiple contrast-enhancing brain lesions (n = 76) on MRI after radiotherapy of brain metastases (predominantly stereotactic radiosurgery) were investigated with dynamic (18)F-FET PET. Maximum and mean tumor-to-brain ratios (TBRmax, TBRmean) of (18)F-FET uptake were determined (20-40 min postinjection) as well as tracer uptake kinetics (ie, time-to-peak and slope of time-activity curves). Diagnoses were confirmed histologically (34%; 26 lesions in 25 patients) or by clinical follow-up (66%; 50 lesions in 37 patients). Diagnostic accuracies of PET parameters for the correct identification of recurrent brain metastasis were evaluated by receiver-operating-characteristic analyses or the chi-square test. RESULTS: TBRs were significantly higher in recurrent metastases (n = 36) than in Radiation injuries (n = 40) (TBRmax 3.3 ± 1.0 vs 2.2 ± 0.4, P < .001; TBRmean 2.2 ± 0.4 vs 1.7 ± 0.3, P < .001). The highest accuracy (88%) for diagnosing local recurrent metastasis could be obtained with TBRs in combination with the slope of time-activity curves (P < .001). CONCLUSIONS: The results of this study confirm previous preliminary observations that the combined evaluation of the TBRs of (18)F-FET uptake and the slope of time-activity curves can differentiate local brain metastasis recurrence from Radiation-induced changes with high accuracy. (18)F-FET PET may thus contribute significantly to the management of patients with brain metastases.
Junru Wang - One of the best experts on this subject based on the ideXlab platform.
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Pharmacological Induction of Transforming Growth Factor-Beta1 in Rat Models Enhances Radiation Injury in the Intestine and the Heart
2016Co-Authors: Marjan Boerma, Junru Wang, Jean-marc Herbert, Vijayalakshmi Sridharan, Martin Hauer-jensenAbstract:Radiation therapy in the treatment of cancer is dose limited by Radiation Injury in normal tissues such as the intestine and the heart. To identify the mechanistic involvement of transforming growth factor-beta 1 (TGF-b1) in intestinal and cardiac Radiation Injury, we studied the influence of pharmacological induction of TGF-b1 with xaliproden (SR 57746A) in rat models of Radiation enteropathy and Radiation-induced heart disease (RIHD). Because it was uncertain to what extent TGF-b induction may enhance Radiation Injury in heart and intestine, animals were exposed to irRadiation schedules that cause mild to moderate (acute) Radiation Injury. In the Radiation enteropathy model, male Sprague-Dawley rats received local irRadiation of a 4-cm loop of rat ileum with 7 once-daily fractions of 5.6 Gy, and intestinal Injury was assessed at 2 weeks and 12 weeks after irRadiation. In the RIHD model, male Sprague-Dawley rats received local heart irRadiation with a single dose of 18 Gy and were followed for 6 months after irRadiation. Rats were treated orally with xaliproden starting 3 days before irRadiation until the end of the experiments. Treatment with xaliproden increased circulating TGF-b1 levels by 300 % and significantly induced expression of TGF-b1 and TGF-b1 target genes in the irradiated intestine and heart. Various Radiation-induced structural changes in the intestine at 2 and 12 weeks were significantly enhanced with TGF-b1 induction. Similarly, in the RIHD model induction of TGF-b1 augmented Radiation-induced changes in cardiac function and myocardial fibrosis. These results lend further support for the direct involvement of TGF-b1 in biological mechanisms of Radiation-induce
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Pharmacological Induction of Transforming Growth Factor-Beta1 in Rat Models Enhances Radiation Injury in the Intestine and the Heart
PloS one, 2013Co-Authors: Marjan Boerma, Junru Wang, Jean-marc Herbert, Vijayalakshmi Sridharan, Martin Hauer-jensenAbstract:Radiation therapy in the treatment of cancer is dose limited by Radiation Injury in normal tissues such as the intestine and the heart. To identify the mechanistic involvement of transforming growth factor-beta 1 (TGF-β1) in intestinal and cardiac Radiation Injury, we studied the influence of pharmacological induction of TGF-β1 with xaliproden (SR 57746A) in rat models of Radiation enteropathy and Radiation-induced heart disease (RIHD). Because it was uncertain to what extent TGF-β induction may enhance Radiation Injury in heart and intestine, animals were exposed to irRadiation schedules that cause mild to moderate (acute) Radiation Injury. In the Radiation enteropathy model, male Sprague-Dawley rats received local irRadiation of a 4-cm loop of rat ileum with 7 once-daily fractions of 5.6 Gy, and intestinal Injury was assessed at 2 weeks and 12 weeks after irRadiation. In the RIHD model, male Sprague-Dawley rats received local heart irRadiation with a single dose of 18 Gy and were followed for 6 months after irRadiation. Rats were treated orally with xaliproden starting 3 days before irRadiation until the end of the experiments. Treatment with xaliproden increased circulating TGF-β1 levels by 300% and significantly induced expression of TGF-β1 and TGF-β1 target genes in the irradiated intestine and heart. Various Radiation-induced structural changes in the intestine at 2 and 12 weeks were significantly enhanced with TGF-β1 induction. Similarly, in the RIHD model induction of TGF-β1 augmented Radiation-induced changes in cardiac function and myocardial fibrosis. These results lend further support for the direct involvement of TGF-β1 in biological mechanisms of Radiation-induced adverse remodeling in the intestine and the heart.
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Activation of Protease Activated Receptor 2 by Exogenous Agonist Exacerbates Early Radiation Injury in Rat Intestine
International journal of radiation oncology biology physics, 2010Co-Authors: Junru Wang, Marjan Boerma, Ashwini Kulkarni, Morley D. Hollenberg, Martin Hauer-jensenAbstract:Purpose Protease-activated receptor-2 (PAR 2 ) is highly expressed throughout the gut and regulates the inflammatory, mitogenic, fibroproliferative, and nociceptive responses to Injury. PAR 2 is strikingly upregulated and exhibits increased activation in response to intestinal irRadiation. We examined the mechanistic significance of Radiation enteropathy development by assessing the effect of exogenous PAR 2 activation. Methods and Materials Rat small bowel was exposed to localized single-dose Radiation (16.5 Gy). The PAR 2 agonist (2-furoyl-LIGRLO-NH 2 ) or vehicle was injected intraperitoneally daily for 3 days before irRadiation (before), for 7 days after irRadiation (after), or both 3 days before and 7 days after irRadiation (before-after). Early and delayed Radiation enteropathy was assessed at 2 and 26 weeks after irRadiation using quantitative histologic examination, morphometry, and immunohistochemical analysis. Results The PAR 2 agonist did not elicit changes in the unirradiated (shielded) intestine. In contrast, in the irradiated intestine procured 2 weeks after irRadiation, administration of the PAR 2 agonist was associated with more severe mucosal Injury and increased intestinal wall thickness in all three treatment groups ( p 2 agonist also exacerbated the Radiation Injury score, serosal thickening, and mucosal inflammation ( p 2 did not affect Radiation-induced intestinal Injury at 26 weeks. Conclusion The results of the present study support a role for PAR 2 activation in the pathogenesis of early Radiation-induced intestinal Injury. Pharmacologic PAR 2 antagonists might have the potential to reduce the intestinal side effects of radiotherapy and/or as countermeasures in radiologic accidents or terrorism scenarios.
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γ tocotrienol ameliorates intestinal Radiation Injury and reduces vascular oxidative stress after total body irRadiation by an hmg coa reductase dependent mechanism
Radiation Research, 2009Co-Authors: Maaike Berbee, Sree K Kumar, Junru Wang, Marjan Boerma, Martin HauerjensenAbstract:Abstract Berbee, M., Fu, Q., Boerma, M., Wang, J., Kumar, K. S. and Hauer-Jensen, M. γ-Tocotrienol Ameliorates Intestinal Radiation Injury and Reduces Vascular Oxidative Stress after Total-Body IrRadiation by an HMG-CoA Reductase-Dependent Mechanism. Radiat. Res. 171, 596–605 (2009). Analogs of vitamin E (tocols) are under development as radioprophylactic agents because of their high efficacy and lack of toxicity. Gamma-tocotrienol (GT3) is of particular interest because, in addition to being an antioxidant, it also inhibits 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase and accumulates to greater extent in endothelial cells than other tocols. We addressed in vivo whether HMG-CoA reductase inhibition contributes to the radioprotection conferred by GT3. Groups of mice were treated with vehicle, mevalonate (the product of the reaction catalyzed by HMG-CoA reductase), GT3 alone or GT3 in combination with mevalonate. Lethality and standard parameters of Injury to the hematopoietic, intestinal and v...
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Up-regulation and Activation of Proteinase-Activated Receptor 2 in Early and Delayed Radiation Injury in the Rat Intestine: Influence of Biological Activators of Proteinase-Activated Receptor 2
Radiation research, 2003Co-Authors: Junru Wang, Morley D. Hollenberg, Huaien Zheng, Suranga J. Wijesuriya, Martin Hauer-jensenAbstract:Abstract Wang, J., Zheng, H., Hollenberg, M. D., Wijesuriya, S. J., Ou, X. and Hauer-Jensen, M. Up-regulation and Activation of Proteinase-Activated Receptor 2 in Early and Delayed Radiation Injury in the Rat Intestine: Influence of Biological Activators of Proteinase-Activated Receptor 2. Radiat. Res. 160, 524–535 (2003). Proteinase-activated receptor 2 (Par2, F2rl1, also designated PAR-2 or PAR2) is prominently expressed in the intestine and has been suggested as a mediator of inflammatory, mitogenic and fibrogenic responses to Injury. Mast cell proteinases and pancreatic trypsin, both of which have been shown to affect the intestinal Radiation response, are the major biological activators of Par2. Conventional Sprague-Dawley rats, mast cell-deficient rats, and rats in which pancreatic exocrine secretion was blocked pharmacologically by octreotide underwent localized irRadiation of a 4-cm loop of small bowel. Radiation Injury was assessed 2 weeks after irRadiation (early, inflammatory phase) and 26 week...
Wei Chen - One of the best experts on this subject based on the ideXlab platform.
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18 f fdopa pet for differentiating recurrent or progressive brain metastatic tumors from late or delayed Radiation Injury after Radiation treatment
The Journal of Nuclear Medicine, 2014Co-Authors: Karlo J Lizarraga, Martin Allenauerbach, Johannes Czernin, Antonio A F Desalles, William H Yong, Michael E Phelps, Wei ChenAbstract:Brain metastases are frequently treated with Radiation. It is critical to distinguish recurrent or progressive brain metastases (RPBM) from late or delayed Radiation Injury (LDRI). The purpose of this study was to examine the diagnostic accuracy as well as the prognostic power of 6-18F-fluoro-l-dopa (18F-FDOPA) PET for differentiating RPBM from LDRI. Methods: Thirty-two patients who had 83 previously irradiated brain metastases and who underwent 18F-FDOPA PET because of an MR imaging–based suggestion of RPBM were studied retrospectively. PET studies were analyzed semiquantitatively (lesion-to-striatum and lesion-to-normal brain tissue ratios based on both maximum and mean standardized uptake values) and visually (4-point scale). The diagnostic accuracy of PET was verified by histopathologic analysis (n = 9) or clinical follow-up (n = 74) on a lesion-by-lesion basis. Receiver operating characteristic curve analysis was used to identify the best diagnostic indices. The power of 18F-FDOPA PET to predict disease progression was evaluated with the Kaplan–Meier and Cox regression methods. Results: The best overall accuracy was achieved by visual scoring, with which a score of 2 or more (lesion uptake greater than or equal to striatum uptake) resulted in a sensitivity of 81.3% and a specificity of 84.3%. Semiquantitative 18F-FDOPA PET uptake indices based on lesion-to-normal brain tissue ratios were significantly higher for RPBM than for LDRI. Among the various predictors tested, 18F-FDOPA PET was the strongest predictor of tumor progression (hazard ratio, 6.26; P
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18 f fdopa pet for differentiating recurrent or progressive brain metastatic tumors from late or delayed Radiation Injury after Radiation treatment
The Journal of Nuclear Medicine, 2014Co-Authors: Karlo J Lizarraga, Martin Allenauerbach, Johannes Czernin, Antonio A F Desalles, William H Yong, Michael E Phelps, Wei ChenAbstract:UNLABELLED: Brain metastases are frequently treated with Radiation. It is critical to distinguish recurrent or progressive brain metastases (RPBM) from late or delayed Radiation Injury (LDRI). The purpose of this study was to examine the diagnostic accuracy as well as the prognostic power of 6-(18)F-fluoro-l-dopa ((18)F-FDOPA) PET for differentiating RPBM from LDRI. METHODS: Thirty-two patients who had 83 previously irradiated brain metastases and who underwent (18)F-FDOPA PET because of an MR imaging-based suggestion of RPBM were studied retrospectively. PET studies were analyzed semiquantitatively (lesion-to-striatum and lesion-to-normal brain tissue ratios based on both maximum and mean standardized uptake values) and visually (4-point scale). The diagnostic accuracy of PET was verified by histopathologic analysis (n = 9) or clinical follow-up (n = 74) on a lesion-by-lesion basis. Receiver operating characteristic curve analysis was used to identify the best diagnostic indices. The power of (18)F-FDOPA PET to predict disease progression was evaluated with the Kaplan-Meier and Cox regression methods. RESULTS: The best overall accuracy was achieved by visual scoring, with which a score of 2 or more (lesion uptake greater than or equal to striatum uptake) resulted in a sensitivity of 81.3% and a specificity of 84.3%. Semiquantitative (18)F-FDOPA PET uptake indices based on lesion-to-normal brain tissue ratios were significantly higher for RPBM than for LDRI. Among the various predictors tested, (18)F-FDOPA PET was the strongest predictor of tumor progression (hazard ratio, 6.26; P < 0.001), and the lesion-to-normal brain tissue ratio or visual score was the best discriminator. The mean time to progression was 4.6 times longer for lesions with negative (18)F-FDOPA PET results than for lesions with positive (18)F-FDOPA PET results (76.5 vs. 16.7 mo; P < 0.001). (18)F-FDOPA PET findings tended to predict overall survival. CONCLUSION: Metabolic imaging with (18)F-FDOPA PET was useful for differentiating RPBM from LDRI. Semiquantitative indices, particularly lesion-to-normal uptake ratios, could be used. A visual score comparing tumor (18)F-FDOPA uptake and striatum (18)F-FDOPA uptake provided the highest sensitivity and specificity and was predictive of disease progression.
