Chromosome transfer experiments link regions on chromosome 7 to radiation resistance in human glioblastoma multiforme

Glioblastoma multiforme (GM) is the most lethal form of brain tumor, with a median survival of approximately 1 year. Treatment options are limited. Radiation therapy is a common form of treatment, but many tumors are resistant. In earlier studies, we found that gain of chromosome 7 is associated with radiation resistance in human primary GM. In this study, we extend that result to a model system in which we transferred chromosome 7 to recipient cells and confirmed radiation resistance as a function of chromosome 7 gain. We identified three candidate regions on chromosome 7 that conferred radiation resistance in our model system.     

Study of the effects of 0.15 terahertz radiation on genome integrity of adult fibroblasts

The applications of Terahertz (THz) technologies have significantly developed in recent years, and the complete understanding of the biological effects of exposure to THz radiation is becoming increasingly important. In a previous study, we found that THz radiation induced genomic damage in fetal fibroblasts. Although these cells demonstrated to be a useful model, exposure of human foetuses to THz radiation is highly improbable. Conversely, THz irradiation of adult dermal tissues is cause of possible concern for some professional and nonprofessional categories. Therefore, we extended our study to the investigation of the effects of THz radiation on adult fibroblasts (HDF). In this work, the effects of THz exposure on HDF cells genome integrity, cell cycle, cytological ultrastructure and proteins expression were assessed. Results of centromere‐negative micronuclei frequencies, phosphorylation of H2AX histone, and telomere length modulation indicated no induction of DNA damage. Concordantly, no changes in the expression of proteins associated with DNA damage sensing and repair were detected. Conversely, our results showed an increase of centromere‐positive micronuclei frequencies and chromosomal nondisjunction events, indicating induction of aneuploidy. Therefore, our results indicate that THz radiation exposure may affect genome integrity through aneugenic effects, and not by DNA breakage. Our findings are compared to published studies, and possible biophysical mechanisms are discussed. Environ. Mol. Mutagen. 59:476–487, 2018. © 2018 Wiley Periodicals, Inc.     

Targeting tumor cells by enhancing radiation sensitivity

The work of Al Knudson created the paradigm in which we see cancer as a result of the accumulation of multiple mutations. Our goal has been to exploit these mutations to develop strategies to enhance therapy for cancer by targeting the malignant cell while sparing the normal tissue. In studying the RAS oncogene, we observed that its expression when activated resulted in enhanced radioresistance. Conversely, inhibition of RAS made cells with activated RAS more radiosensitive. Hence, we postulated that it would be possible to sensitize tumors with RAS mutations to radiation without affecting the sensitivity of the normal tissue in patients with such tumors. This proved to be the case in animal models and has led to current clinical trials. These studies raised the question of identifying the downstream effectors of RAS that are responsible for altering the radiosensitivity of cells. We have found that phosphoinositide-3-kinase (PI3 kinase) is a critical component of this pathway. Blocking PI3 kinase enhanced the radiation response in vitro or in vivo of cells actively signaling through that pathway, but did not affect cells not actively signaling through PI3 kinase at the time of irradiation. Identification of tumors with active signaling in this pathway by immunohistochemical staining for phosphorylated AKT, the downstream target of PI3 kinase correlated with those patients for which radiation failed to achieve local control. Thus, characterization of the active signaling pathways in a given tumor might enable the selection of patients likely to respond to radiation. Pathways upstream from RAS may also be useful targets to consider for enhancing radiation therapy. Epidermal growth factor receptor (EGFR), which is upstream of PI3 kinase, may also mediate resistance through a common pathway. In addition to EGFR and RAS, PTEN can also regulate the PI3 kinase pathway. Identifying a common signal for EGFR, RAS, and PTEN that results in radiation resistance may uncover targets for developing molecular-based radiosensitization protocols for tumors resistant to radiation and thus lead to improvement of local control.     

Quantifying tumor-selective radiation dose enhancements using gold nanoparticles: a monte carlo simulation study

Gold nanoparticles can enhance the biological effective dose of radiation delivered to tumors, but few data exist to quantify this effect. The purpose of this project was to build a Monte Carlo simulation model to study the degree of dose enhancement achievable with gold nanoparticles. A Monte Carlo simulation model was first built using Geant4 code. An Ir-192 brachytherapy source in a water phantom was simulated and the calculation model was first validated against previously published data. We then introduced up to 10¹³ gold nanospheres per cm³ into the water phantom and examined their dose enhancement effect. We compared this enhancement against a gold-water mixture model that has been previously used to attempt to quantify nanoparticle dose enhancement. In our benchmark test, dose-rate constant, radial dose function, and two-dimensional anisotropy function calculated with our model were within 2% of those reported previously. Using our simulation model we found that the radiation dose was enhanced up to 60% with 10¹³ gold nanospheres per cm³ (9.6% by weight) in a water phantom selectively around the nanospheres. The comparison study indicated that our model more accurately calculated the dose enhancement effect and that previous methodologies overestimated the dose enhancement up to 16%. Monte Carlo calculations demonstrate that biologically-relevant radiation dose enhancement can be achieved with the use of gold nanospheres. Selective tumor labeling with gold nanospheres may be a strategy for clinically enhancing radiation effects. This study was partially funded by a grant from the U. S. Department of Defense Breast Cancer Research Program (W81XWH-06-1-0672) and by the institutional core grant (CA 16672). The authors also wish to acknowledge the Department of Scientific Publications at The University of Texas M. D. Anderson Cancer Center for its editorial assistance during the preparation of this article.     

In vivo study of human skin using pulsed terahertz radiation

Studies in terahertz (THz) imaging have revealed a significant difference between skin cancer (basal cell carcinoma) and healthy tissue. Since water has strong absorptions at THz frequencies and tumours tend to have different water content from normal tissue, a likely contrast mechanism is variation in water content. Thus, we have previously devised a finite difference time-domain (FDTD) model which is able to closely simulate the interaction of THz radiation with water. In this work we investigate the interaction of THz radiation with normal human skin on the forearm and palm of the hand in vivo. We conduct the first ever systematic in vivo study of the response of THz radiation to normal skin. We take in vivo reflection measurements of normal skin on the forearm and palm of the hand of 20 volunteers. We compare individual examples of THz responses with the mean response for the areas of skin under investigation. Using the in vivo data, we demonstrate that the FDTD model can be applied to biological tissue. In particular, we successfully simulate the interaction of THz radiation with the volar forearm. Understanding the interaction of THz radiation with normal skin will form a step towards developing improved imaging algorithms for diagnostic detection of skin cancer and other tissue disorders using THz radiation.     

Effect of low-intensity infrared and millimeter radiation on higher plants' biopotentials.

This article studies the effect of local low-intensity electromagnetic radiation on the bioelectric responses of plants. In our investigation, we used thirty-three wavelengths in the visible and infrared spectrurm regions as well as three wavelengths in the millimeter spectrum region. As a result, we obtained the bioelectric responses of plants to electromagnetic radiation not only in the absorption region of cellular pigments (such as chlorophyll, flavin, and phytochrome) but also in the absorption region of water molecules.     

Beam orientation optimization in intensity-modulated radiation treatment planning

Beam direction optimization is an important problem in radiation therapy. In intensity modulated radiation therapy (IMRT), the difficulty for computer optimization of the beam directions arises from the fact that they are coupled with the intensity profiles of the incident beams. In order to obtain the optimal incident beam directions using iterative or stochastic methods, the beam profiles ought to be optimized after every change of beam configuration. In this paper we report an effective algorithm to optimize gantry angles for IMRT. In our calculation the gantry angles and the beam profiles (beamlet weights) were treated as two separate groups of variables. The gantry angles were sampled according to a simulated annealing algorithm. For each sampled beam configuration, beam profile calculation was done using a fast filtered backprojection (FBP) method. Simulated annealing was also used for beam profile optimization to examine the performance of the FBP for beam orientation optimization. Relative importance factors were incorporated into the objective function to control the relative importance of the target and the sensitive structures. Minimization of the objective function resulted in the best possible beam orientations and beam profiles judged by the given objective function. The algorithm was applied to several model problems and the results showed that the approach has potential for IMRT applications.     

Hypothetical HTLV-I induction by ionizing radiation

Some laboratories have reported HTLV-I genome integration in cancer patients diagnosed with neoplasms of cervix and uterus. Usually, cancer patients undergo radiotherapy besides chemotherapy and surgery. It is hypothesized that radiation exposure would induce HTLV-I genome generation/activation, nevertheless there is not any report on experimental procedures trying to demonstrate HTLV-I gene expression in cells exposed to ionizing radiation. Anyway, earlier experimental works by Lieberman and Kaplan in 1959 succeeded to isolate retroviral particles, the radiation leukemia virus (RadLV), from thymic lymphomas of X-ray-irradiated C57BL/Ka mice, assuming that RadLV activated in the host by ionizing radiation, is released and transported to the thymus, where lymphoblasts, generated during the postradiation recovery phase, constitute an optimal target cell population for both replication of and eventual transformation by virus. Recent studies claim that besides RadLV, another retrovirus (RadLV-0) also induced by ionizing radiation is expressed and would be responsible for transformed cells of bone marrow origin. Epidemiological studies coincidentally point out to high incidence of HTLV-I infection in geographic areas displaying significant levels of radioactivity contamination as in Central Africa, Japan Islands and Mururoa Atoll. In our research work, we detected HTLV-I antibodies and viral genome integration in cancer patients of cervix and uterus and health care workers, whose had been exposed to ionizing radiation during radiotherapeutic procedures. Recombinational events among endogenous retrovirus and other retrogenic elements in the host cell genome under the bombardment of ionizing radiation from different sources could have optimized the phenomena occurrence or even ignited them to happen, generating HTLV-I genome, related viral peptides and virions. Therefore, it is feasible that exposure to ionizing radiation during therapeutic procedures could generate HTLV-I genome or induce the virus to be expressed in cells of cancer patients submitted to radiotherapy as also in healthy subjects under the same conditions, in artificial or natural radiation environment.     

The effect of stochastic fluctuation in radiation dose-rate on cell survival following fractionated radiation therapy

In radiobiological models, it is often assumed that the radiation dose rate remains constant during the course of radiation delivery. However, instantaneous radiation dose rate undergoes random (stochastic) temporal fluctuation. The effect of stochastic dose rate in fractionated radiation therapy is unknown and there has been no analytical formulation of stochastic dose-rate fluctuation effect in fractionated radiation therapy which we endeavor to pursue here. We have obtained the quantitative expression of cellular survival fraction considering stochastic temporal fluctuation or noise in dose rate. We have shown that the constant dose-rate approximation overestimates the survival fraction compared to that under stochastic dose rate in a fractionated radiation therapy situation and this overestimation effect increases appreciably with the increase in the fluctuation level in dose rate. However, for a given level of fluctuation in dose rate, overestimation of survival fraction also depends on the value of cellular radiation sensitivity parameter β and the repair rate of DNA lesion. This overestimation effect is higher for the cells which have a higher value of β parameter or have a lower repair rate. Our study draws attention to stochastic temporal fluctuation in the radiation dose rate and its potential contribution to cell survival following fractionated radiotherapy.     

Patient specification quality assurance for glioblastoma multiforme brain tumors treated with intensity modulated radiation therapy

The aim of this study was to evaluate the significance of performing patient specification quality assurance for patients diagnosed with glioblastoma multiforme treated with intensity modulated radiation therapy. The study evaluated ten intensity modulated radiation therapy treatment plans using 10 MV beams, a total dose of 60 Gy (2 Gy/fraction, five fractions a week for a total of six weeks treatment). For the quality assurance protocol we used a two-dimensional ionization-chamber array (2D-ARRAY). The results showed a very good agreement between the measured dose and the pretreatment planned dose. All the plans passed >95% gamma criterion with pixels within 5% dose difference and 3 mm distance to agreement. We concluded that using the 2D-ARRAY ion chamber for intensity modulated radiation therapy is an important step for intensity modulated radiation therapy treatment plans, and this study has shown that our treatment planning for intensity modulated radiation therapy is accurately done.     

Film dosimetry for intensity modulated radiation therapy: dosimetric evaluation

X-ray film has been used for the dosimetry of intensity modulated radiation therapy (IMRT). However, the over-response of the film to low-energy photons is a significant problem in photon beam dosimetry, especially in regions outside penumbra. In IMRT, the radiation field consists of multiple small fields and their outside-penumbra regions; thus, the film dosimetry, for it involves the source of over-response in its radiation field. In this study we aim to verify and possibly improve film dosimetry for IMRT. Two types of modulated beams were constructed by combining five to seven different static radiation fields using 6 MV x rays. For verifying film dosimetry, x-ray films and an ion chamber were used to measure dose profiles at various depths in a phantom. The film setups include both parallel and perpendicular arrangements against the beam incident direction. In addition, to reduce an over-response, we placed 0.01 in. (0.25 mm) thick lead filters on both sides of the film. Compared with ion-chamber measurement, measured dose profiles showed the film over-response at outside-penumbra and low-dose regions. The error increased with depths and approached 15% as a maximum for the field size of 15 cm x 15 cm at 10 cm depth. The use of filters reduced the error down to 3%. In this study we demonstrated that film dosimetry for IMRT involves sources of error due to its over-response to low-energy photons, with the error most transparent in the low-dose region. The use of filters could enhance the accuracy in film dosimetry for IMRT. In this regard, the use of an optimal filter condition is recommended.     

Idiopathic pneumonia syndrome after allogeneic bone marrow transplantation in mice. Role of pretransplant radiation conditioning.

Idiopathic pneumonia syndrome (IPS) is a significant clinical problem encountered among patients treated with bone marrow transplantation (BMT). IPS is identified as an inflammatory lung disease characterized by diffuse interstitial pneumonitis and alveolitis leading to interstitial fibrosis in the absence of an identifiable infectious agent. In an earlier study we characterized a murine model of IPS following allogeneic BMT that exhibits several features of human IPS. In this report we show that the lung represents a unique target of post-BMT disease in this model. The kinetics of developing lung disease were found to be markedly different from the kinetics of graft-versus-host disease in other tissues such as liver, colon, ear, skin, and tongue. Mice transplanted by our standard protocol with T-cell-depleted semiallogeneic donor bone marrow plus donor spleen cells in the absence of pretransplant radiation conditioning did not develop lung inflammation or fibrosis characteristic of IPS. Pretransplant radiation conditioning in the absence of BMT also failed to cause IPS, demonstrating an important role for radiation conditioning in the development of BMT-related IPS. The occurrence of lung disease post-BMT was found to be dependent on radiation conditioning in a dose-dependent manner. Finally, thoracic irradiation alone was demonstrated to be sufficient in causing IPS in mice transplanted with bone marrow plus spleen cells, albeit with reduced severity. Based on these findings, we conclude that pretransplant radiation conditioning plays an important role in the development of IPS following allogeneic BMT.     

Large deformation three-dimensional image registration in image-guided radiation therapy

In this paper, we present and validate a framework, based on deformable image registration, for automatic processing of serial three-dimensional CT images used in image-guided radiation therapy. A major assumption in deformable image registration has been that, if two images are being registered, every point of one image corresponds appropriately to some point in the other. For intra-treatment images of the prostate, however, this assumption is violated by the variable presence of bowel gas. The framework presented here explicitly extends previous deformable image registration algorithms to accommodate such regions in the image for which no correspondence exists. We show how to use our registration technique as a tool for organ segmentation, and present a statistical analysis of this segmentation method, validating it by comparison with multiple human raters. We also show how the deformable registration technique can be used to determine the dosimetric effect of a given plan in the presence of non-rigid tissue motion. In addition to dose accumulation, we describe a method for estimating the biological effects of tissue motion using a linear-quadratic model. This work is described in the context of a prostate treatment protocol, but it is of general applicability.     

Response of terrestrial microorganisms to ultraviolet-B radiation in ecosystems

Recent studies suggest that ultraviolet-B radiation, a major component of global climate change, can affect the community structure, biomass and functioning of terrestrial microorganisms. In this report, these studies are reviewed and gaps in our understanding highlighted so that future research can provide more conclusive evidence on the mechanisms and wider ecological implications of the impacts of elevated ultraviolet-B radiation on terrestrial microorganisms.     

Evaluation of stray radiofrequency radiation emitted by electrosurgical devices

Electrosurgery refers to the passage of a high-frequency, high-voltage electrical current through the body to achieve the desired surgical effects. At the same time, these procedures are accompanied by a general increase of the electromagnetic field in an operating room that may expose both patients and personnel to relatively high levels of radiofrequency radiation. In the first part of this study, we have taken into account the radiation emitted by different monopolar electrosurgical devices, evaluating the electromagnetic field strength delivered by an electrosurgical handle and straying from units and other electrosurgical accessories. As a summary, in the worst case a surgeon's hands are exposed to a continuous and pulsed RF wave whose magnetic field strength is 0.75 A m(-1) (E-field 400 V m(-1)). Occasionally stray radiation may exceed ICNIRP's occupational exposure guidelines, especially close to the patient return plate. In the second part of this paper, we have analysed areas of particular concern to prevent electromagnetic interference with some life-support devices (ventilators and electrocardiographic devices), which have failed to operate correctly. Most clinically relevant interference occurred when an electrosurgery device was used within 0.3 m of medical equipment. In the appendix, we suggest some practical recommendations intended to minimize the potential for electromagnetic hazards due to therapeutic application of RF energy.     

Transformation of human mesenchymal stem cells in radiation carcinogenesis: long-term effect of ionizing radiation

Increasing evidence on cancer stem cells suggest that stem cells are susceptive to carcinogenesis and consequently can be the origin of many cancers. We have recently established a telomerase-transduced human mesenchymal stem cell line and subsequently irradiated this in order to achieve malignant transformation. In the present study, we analyzed the long-term effect of ionizing radiation on these cells and investigate whether radiation can trigger tumor development. The cells were irradiated with a low (2.5 Gy) and a high (15 Gy) dose of gamma-rays and followed for up to 6 months after radiation. A subclone of the cells irradiated with 2.5 Gy of gamma-rays formed tumors after implantation to severe combined immunodeficiency mice. During the process of transformation, the cells showed accelerated telomere shortening, increased levels of anaphase bridges and a shift from balanced to unbalanced translocations. The tumor suppressor genes p53 and p21(CIP1) functioned normally throughout the study. Our observations indicate that radiation destabilized the telomeres and that the presence of uncapped telomeres initiated fusion-break-fusion cycles, resulting in increased chromosomal instability and tumor formation. Thus, bone marrow-derived human mesenchymal stem cells are capable of exhibiting a malignant phenotype.     

Arc-modulated radiation therapy (AMRT): a single-arc form of intensity-modulated arc therapy

Arc-modulated radiation therapy (AMRT) is a novel rotational intensity-modulated radiation therapy (IMRT) technique developed for a clinical linear accelerator that aims to deliver highly conformal radiation treatment using just one arc of gantry rotation. Compared to fixed-gantry IMRT and the multiple-arc intensity-modulated arc therapy (IMAT) techniques, AMRT promises the same treatment quality with a single-arc delivery. In this paper, we present a treatment planning scheme for AMRT, which addresses the challenges in inverse planning, leaf sequencing and dose calculation. The feasibility and performance of this AMRT treatment planning scheme have been verified with multiple clinical cases of various sites on Varian linear accelerators.     

Effects of infrared radiation on skin photo-aging and pigmentation

Infrared radiation is increasingly and uncritically used for cosmetic and wellness purposes, despite the poorly understood biologic effects of such treatments on humans. In the present study, we investigated the effects of infrared radiation on collagen and elastin production in dermal fibroblasts, as well as the clinical and histopathologic effects of infrared radiation on photo-aged facial skin lesions. In order to determine the effects of infrared radiation on collagen and elastin production, dermal fibroblasts were exposed to infrared radiation for varying lengths of time and collagen and elastin contents were subsequently determined. Additionally, 20 patients with mild to moderate facial wrinkles and hyperpigmented lesions received daily treatments of far infrared radiation (900 to 1000 microm) for six-months. During the treatment, patients and a medical observer conducted independent photographic and clinical evaluations every 4 weeks, and skin biopsies were obtained for histological analysis at baseline and one month post-treatment. We found that the content of collagen and elastin produced by the fibroblasts increased after infrared radiation, and that this increase was proportional to the duration of irradiation exposure. Following 6 months of treatment, all patients reported good (51-75%) improvements in skin texture and roughness. Additionally, patients noted fair (25-50%) improvement in color tone of the skin; however, improvements in hyperpigmented lesions were not observed. Objective medical evaluation of the patients indicated that roughness and laxity were fairly improved, but there was no significant improvement in hyperpigmented lesions. Histological examination failed to reveal any differences as well. These results suggest that infrared radiation may have beneficial effects on skin texture and wrinkles by increasing collagen and elastin contents from the stimulated fibroblasts. Therefore, skin treatment with infrared radiation may be an effective and safe non-ablative remodeling method, and may also be useful in the treatment of photo-aged skin.     

Beam orientation optimization for intensity modulated radiation therapy using adaptive l(2,1)-minimization

Beam orientation optimization (BOO) is a key component in the process of intensity modulated radiation therapy treatment planning. It determines to what degree one can achieve a good treatment plan in the subsequent plan optimization process. In this paper, we have developed a BOO algorithm via adaptive l(2, 1)-minimization. Specifically, we introduce a sparsity objective function term into our model which contains weighting factors for each beam angle adaptively adjusted during the optimization process. Such an objective function favors a small number of beam angles. By optimizing a total objective function consisting of a dosimetric term and the sparsity term, we are able to identify unimportant beam angles and gradually remove them without largely sacrificing the dosimetric objective. In one typical prostate case, the convergence property of our algorithm, as well as how beam angles are selected during the optimization process, is demonstrated. Fluence map optimization (FMO) is then performed based on the optimized beam angles. The resulting plan quality is presented and is found to be better than that of equiangular beam orientations. We have further systematically validated our algorithm in the contexts of 5-9 coplanar beams for five prostate cases and one head and neck case. For each case, the final FMO objective function value is used to compare the optimized beam orientations with the equiangular ones. It is found that, in the majority of cases tested, our BOO algorithm leads to beam configurations which attain lower FMO objective function values than those of corresponding equiangular cases, indicating the effectiveness of our BOO algorithm. Superior plan qualities are also demonstrated by comparing DVH curves between BOO plans and equiangular plans.