Targeting of cellular redox metabolism for mitigation of radiation injury

Accidental exposure to ionizing radiation is a serious concern to human life. Studies on the mitigation of side effects following exposure to accidental radiation events are ongoing. Recent studies have shown that radiation can activate several signaling pathways, leading to changes in the metabolism of free radicals including reactive oxygen species (ROS) and nitric oxide (NO). Cellular and molecular mechanisms show that radiation can cause disruption of normal reduction/oxidation (redox) system. Mitochondria malfunction following exposure to radiation and mutations in mitochondria DNA (mtDNA) have a key role in chronic oxidative stress. Furthermore, exposure to radiation leads to infiltration of inflammatory cells such as macrophages, lymphocytes and mast cells, which are important sources of ROS and NO. These cells generate free radicals via upregulation of some pro-oxidant enzymes such as NADPH oxidases, inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2). Epigenetic changes also have a key role in a similar way. Other mediators such as mammalian target of rapamycin (mTOR) and peroxisome proliferator-activated receptor (PPAR), which are involved in the normal metabolism of cells have also been shown to regulate cell death following exposure to radiation. These mechanisms are tissue specific. Inhibition or activation of each of these targets can be suggested for mitigation of radiation injury in a specific tissue. In the current paper, we review the cellular and molecular changes in the metabolism of cells and ROS/NO following exposure to radiation. Furthermore, the possible strategies for mitigation of radiation injury through modulation of cellular metabolism in irradiated organs will be discussed. © 2020 Elsevier Inc

TGF-β in radiotherapy: Mechanisms of tumor resistance and normal tissues injury

Emerging evidences show that changes in tumor stroma can adapt cancer cells to radiotherapy, thereby leading to a reduction in tumor response to treatment. On the other hand, radiotherapy is associated with severe reactions in normal tissues which limit the amount radiation dose received by tumor. These challenges open a window in radiobiology and radiation oncology to explore mechanisms for improving tumor response and also alleviate side effects of radiotherapy. Transforming growth factor beta (TGF-β) is a well-known and multitasking cytokine that regulates a wide range of reactions and interactions within tumor and normal tissues. Within tumor microenvironment (TME), TGF-β is the most potent suppressor of immune system activity against cancer cells. This effect is mediated through stimulation of CD4+ which differentiates to T regulatory cells (Tregs), infiltration of fibroblasts and differentiation into cancer associated fibroblasts (CAFs), and also polarization of macrophages to M2 cells. These changes lead to suppression of cytotoxic CD8 + T lymphocytes (CTLs) and natural killer (NK) cells to kill cancer cells. TGF-β also plays a key role in the angiogenesis, invasion and DNA damage responses (DDR) in cancer cells. In normal tissues, TGF-β triggers the expression of a wide range of pro-oxidant and pro-fibrosis genes, leading to fibrosis, genomic instability and some other side effects. These properties of TGF-β make it a potential target to preserve normal tissues and sensitize tumor via its inhibition. In the current review, we aim to explain the mechanisms of upregulation of TGF-β and its consequences in both tumor and normal tissues. © 2020 Elsevier Lt

A full quantitative analysis of 18 MV photon beam from 2100 C/D-Varian clinical linear accelerator with and without flattening filter

Background: During intensity modulated radiation therapy (IMRT) technique, theoretically, presence of flattening filter (FF) across the beamline of clinical linear accelerator (linac) is not essential to obtain uniform lateral profiles due to intensity modulation of photon beams by multileaf collimators (MLCs). The aim of this study was to investigate the dosimetrical properties of 18 MV photon beam-Varian linac with and without FF. Materials and Methods: All dose measurements were performed on 18 MV, FF mode-Varian 2100C/D linac. The FF and flattening filter free (FFF) modes of linac were modeled by MCNPX 2.4. code. The photon and contaminant electrons spectra, dose rate, present depth doses (PDD), lateral dose profiles, total and collimator scatter factors and out of field doses were calculated and compared with and without FF. Results: Removing the FF increased the photon and contaminant electron fluences by factors of 5.48 and 3.94 for a 5 � 5 cm2 field size, respectively. The surface dose increased up to 155. The flatness of dose profile was disturbed and deteriorated with increase of field size. Despite the dependence of the total scattering factor on field size, the variation of collimator scattering factors was neglected. The out-of-field dose decreased about 81.5 for a 5 � 5 cm2 field size. Conclusion: Removing FF from the linac head increases the dose rate and decreases the out-of-field dose, but the increased skin dose and deteriorated flatness of lateral dose profile are the main disadvantages of the FFF mode. © 2019 Novin Medical Radiation Institute. All rights reserved

TGF-β in radiotherapy: Mechanisms of tumor resistance and normal tissues injury

Emerging evidences show that changes in tumor stroma can adapt cancer cells to radiotherapy, thereby leading to a reduction in tumor response to treatment. On the other hand, radiotherapy is associated with severe reactions in normal tissues which limit the amount radiation dose received by tumor. These challenges open a window in radiobiology and radiation oncology to explore mechanisms for improving tumor response and also alleviate side effects of radiotherapy. Transforming growth factor beta (TGF-β) is a well-known and multitasking cytokine that regulates a wide range of reactions and interactions within tumor and normal tissues. Within tumor microenvironment (TME), TGF-β is the most potent suppressor of immune system activity against cancer cells. This effect is mediated through stimulation of CD4+ which differentiates to T regulatory cells (Tregs), infiltration of fibroblasts and differentiation into cancer associated fibroblasts (CAFs), and also polarization of macrophages to M2 cells. These changes lead to suppression of cytotoxic CD8 + T lymphocytes (CTLs) and natural killer (NK) cells to kill cancer cells. TGF-β also plays a key role in the angiogenesis, invasion and DNA damage responses (DDR) in cancer cells. In normal tissues, TGF-β triggers the expression of a wide range of pro-oxidant and pro-fibrosis genes, leading to fibrosis, genomic instability and some other side effects. These properties of TGF-β make it a potential target to preserve normal tissues and sensitize tumor via its inhibition. In the current review, we aim to explain the mechanisms of upregulation of TGF-β and its consequences in both tumor and normal tissues. © 2020 Elsevier Lt

Mapping geographical inequalities in childhood diarrhoeal morbidity and mortality in low-income and middle-income countries, 2000–17 : analysis for the Global Burden of Disease Study 2017

Background Across low-income and middle-income countries (LMICs), one in ten deaths in children younger than 5 years is attributable to diarrhoea. The substantial between-country variation in both diarrhoea incidence and mortality is attributable to interventions that protect children, prevent infection, and treat disease. Identifying subnational regions with the highest burden and mapping associated risk factors can aid in reducing preventable childhood diarrhoea. Methods We used Bayesian model-based geostatistics and a geolocated dataset comprising 15 072 746 children younger than 5 years from 466 surveys in 94 LMICs, in combination with findings of the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2017, to estimate posterior distributions of diarrhoea prevalence, incidence, and mortality from 2000 to 2017. From these data, we estimated the burden of diarrhoea at varying subnational levels (termed units) by spatially aggregating draws, and we investigated the drivers of subnational patterns by creating aggregated risk factor estimates. Findings The greatest declines in diarrhoeal mortality were seen in south and southeast Asia and South America, where 54·0% (95% uncertainty interval [UI] 38·1–65·8), 17·4% (7·7–28·4), and 59·5% (34·2–86·9) of units, respectively, recorded decreases in deaths from diarrhoea greater than 10%. Although children in much of Africa remain at high risk of death due to diarrhoea, regions with the most deaths were outside Africa, with the highest mortality units located in Pakistan. Indonesia showed the greatest within-country geographical inequality; some regions had mortality rates nearly four times the average country rate. Reductions in mortality were correlated to improvements in water, sanitation, and hygiene (WASH) or reductions in child growth failure (CGF). Similarly, most high-risk areas had poor WASH, high CGF, or low oral rehydration therapy coverage. Interpretation By co-analysing geospatial trends in diarrhoeal burden and its key risk factors, we could assess candidate drivers of subnational death reduction. Further, by doing a counterfactual analysis of the remaining disease burden using key risk factors, we identified potential intervention strategies for vulnerable populations. In view of the demands for limited resources in LMICs, accurately quantifying the burden of diarrhoea and its drivers is important for precision public health

Mapping 123 million neonatal, infant and child deaths between 2000 and 2017

Since 2000, many countries have achieved considerable success in improving child survival, but localized progress remains unclear. To inform efforts towards United Nations Sustainable Development Goal 3.2—to end preventable child deaths by 2030—we need consistently estimated data at the subnational level regarding child mortality rates and trends. Here we quantified, for the period 2000–2017, the subnational variation in mortality rates and number of deaths of neonates, infants and children under 5 years of age within 99 low- and middle-income countries using a geostatistical survival model. We estimated that 32% of children under 5 in these countries lived in districts that had attained rates of 25 or fewer child deaths per 1,000 live births by 2017, and that 58% of child deaths between 2000 and 2017 in these countries could have been averted in the absence of geographical inequality. This study enables the identification of high-mortality clusters, patterns of progress and geographical inequalities to inform appropriate investments and implementations that will help to improve the health of all populations

Dosimetric characteristics of 6 MV modified beams by physical wedges of a siemens linear accelerator

Physical wedges still can be used as missing tissue compensators or filters to alter the shape of isodose curves in a target volume to reach an optimal radiotherapy plan without creating a hotspot. The aim of this study was to investigate the dosimetric properties of physical wedges filters such as off-axis photon fluence, photon spectrum, output factor and half value layer. The photon beam quality of a 6 MV Primus Siemens modified by 150 and 450 physical wedges was studied with BEAMnrc Monte Carlo (MC) code. The calculated present depth dose and dose profile curves for open and wedged photon beam were in good agreement with the measurements. Increase of wedge angle increased the beam hardening and this effect was more pronounced at the heal region. Using such an accurate MC model to determine of wedge factors and implementation of it as a calculation algorithm in the future treatment planning systems is recommended

Determination of initial beam parameters of Varian 2100 CD Linac for various therapeutic electrons using PRIMO

The aim of the present research was to establish primary characteristics of electron beams for a Varian 2100C/D linear accelerator with recently developed PRIMO Monte Carlo software and to verify relations between electron energy and dose distribution. To maintain conformity of simulated and measured dose curves within 1/1mm, mean energy, Full Width at Half Maximum (FWHM) of energy and focal spot FWHM of initial beam were changed iteratively. Mean and most probable energies were extracted from validated phase spaces and compared with related empirical equation results. To explain the importance of correct estimation of primary energy on a clinical case, computed tomography images of a thorax phantom were imported in PRIMO. Dose distributions and dose volume histogram (DVH) curves were compared between validated and artificial cases with overestimated energy. Initial mean energies were obtained of 6.68, 9.73, 13.2 and 16.4 MeV for 6, 9, 12 and 15 nominal energies, respectively. Energy FWHM reduced with increase in energy. Three mm focal spot FWHM for 9 MeV and 4 mm for other energies made proper matches of simulated and measured profiles. In addition, the maximum difference of calculated mean electrons energy at the phantom surface with empirical equation was 2.2 percent. Finally, clear differences in DVH curves of validated and artificial energy were observed as heterogeneity indexes were 0.15 for 7.21 MeV and 0.25 for 6.68 MeV. The Monte Carlo model presented in PRIMO for Varian 2100 CD was precisely validated. IAEA polynomial equations estimated mean energy more accurately than a known linear one. Small displacement of R50 changed DVH curves and homogeneity indexes. PRIMO is a user-friendly software which has suitable capabilities to calculate dose distribution in water phantoms or computerized tomographic volumes accurately

The Effect of Gold Nanoparticle on Electrical Impedance of Tissue on Low Frequency Ranges

Introduction: Electrical impedance of tissues on low frequencies includes useful information about functional and structural changes in tissues. This property is used in Electrical Impedance Tomography (EIT) imaging modality for the detection of lesions in tissues. Objective: The goal of this article is to study changes in electrical impedance of tissues in the presence of gold nanoparticles. Materials and Methods: Spherical gold nanoparticles with size of 20-25 nm were synthesized with Turkevich method. Size distribution and shape of nanoparticles were characterized by transmission electron microscopy (TEM). Electrical impedance of two types of phantoms (chicken fat and muscle paste tissues) was measured by 4-electrode method with and without gold nanoparticles. Results: Results demonstrate a reduction in electrical impedance of tissues in the presence of gold nanoparticles. However, this reduction is not the same for fat and muscle tissues. Reductions in resistive impedance are for fat and muscle tissues on the frequency of 1 KHz, respectively. A reduction in electrical impedance is accompanied by a rise in electrical conductance leading to increase in EIT signal. Conclusion: As signal enhancement is different for fat and muscle tissues; presence of gold nanoparticles could be used to improve EIT image contrast

Targets for protection and mitigation of radiation injury

Protection of normal tissues against toxic effects of ionizing radiation is a critical issue in clinical and environmental radiobiology. Investigations in recent decades have suggested potential targets that are involved in the protection against radiation-induced damages to normal tissues and can be proposed for mitigation of radiation injury. Emerging evidences have been shown to be in contrast to an old dogma in radiation biology; a major amount of reactive oxygen species (ROS) production and cell toxicity occur during some hours to years after exposure to ionizing radiation. This can be attributed to upregulation of inflammatory and fibrosis mediators, epigenetic changes and disruption of the normal metabolism of oxygen. In the current review, we explain the cellular and molecular changes following exposure of normal tissues to ionizing radiation. Furthermore, we review potential targets that can be proposed for protection and mitigation of radiation toxicity. © 2020, Springer Nature Switzerland AG