The potential role of environmental exposures and genomic signaling in development of central nervous system tumors

The etiology of central nervous system tumors (CNSTs) is mainly unknown. Aside from extremely rare genetic conditions, such as neurofibromatosis and tuberous sclerosis, the only unequivocally identified risk factor is exposure to ionizing radiation, and this explains only a very small fraction of cases. Using meta-analysis, gene networking and bioinformatics methods, this dissertation explored the hypothesis that environmental exposures produce genetic and epigenetic alterations that may be involved in the etiology of CNSTs. A meta-analysis of epidemiological studies of pesticides and pediatric brain tumors revealed a significantly increased risk of brain tumors among children whose mothers had farm-related exposures during pregnancy. A dose response was recognized when this risk estimate was compared to those for risk of brain tumors from maternal exposure to non-agricultural pesticides during pregnancy, and risk of brain tumors among children exposed to agricultural activities. Through meta-analysis of several microarray studies which compared normal tissue to astrocytomas, we were able to identify a list of 554 genes which were differentially expressed in the majority of astrocytomas. Many of these genes have in fact been implicated in development of astrocytoma, including EGFR, HIF-1α, c-Myc, WNT5A, and IDH3A. Reverse engineering of these 554 genes using Bayesian network analysis produced a gene network for each grade of astrocytoma (Grade I-IV), and ‘key genes’ within each grade were identified. Genes found to be most influential to development of the highest grade of astrocytoma, Glioblastoma multiforme (GBM) were: COL4A1, EGFR, BTF3, MPP2, RAB31, CDK4, CD99, ANXA2, TOP2A, and SERBP1. Lastly, bioinformatics analysis of environmental databases and curated published results on GBM was able to identify numerous potential pathways and geneenvironment interactions that may play key roles in astrocytoma development. Findings from this research have strong potential to advance our understanding of the etiology and susceptibility to CNSTs. Validation of our ‘key genes’ and pathways could potentially lead to useful tools for early detection and novel therapeutic options for these tumors.

Influência da radiação ionizante natural no açude do boqueirão (RN): avaliação de risco saúde/ambiente

The contamination of water bodies with toxic substances causes a decrease in water quality, representing a risk to public health. In this context, human activities are generally seen as the main sources of water degradation. However, elements found naturally in the environment can also compromise water quality. Thus, the Boqueirão‘s dam, located in the municipality of Parelhas (RN, Brazil), was chosen as area for the development of this study, as its geological region is rich in the emission of natural ionizing radiation that produces byproducts like lead and Radon. Moreover, the area has a strong human influence that enhances the risks of pollutant discharge in this body of water.Thus, the objectives of this study were centered (i) in the analysis of risk perception in the city of Parelhas (RN/Brasil) due to the use of the water from the Boqueirão Dam; and (ii) in the assessment of water quality in the Dam using methods that quantify, mainly, heavy metals and radiation levels, as well as these toxics potential of inducing mutations on genetic material. The analysis of risk perception showed that the population in the city of Parelhas can perceive a risk in using the water from the dam and that they can recognize factors that influence the water quality. Regarding the second objective, the set of data point to the contamination of the Dam by heavy metals, as well as levels of radioactive parcicles and Radon – also present in high concentrations in outdoor air and on soil. Thus, it is possible to infer that the population residing in this area is subjected to injuries caused by exposure to natural and anthropogenic contamination. Our findings corroborate with the perception of the population regarding the risks associated with the use of the Dam for several types of activities. It is expected that the information gathered in this study can substantiate activities and future researches in this semiarid region in the Rio Grande do Norte/Brazil. Also, that the set of data can enable a better understanding of the specific toxicological scenario of risk found for the population and the effect of the contamination for the biota, which aids the development of a future risk assessment and a consequent management of this local issue.

Sistemas de cálculo, análise e operação virtual: interferências de campos elétricos e magnéticos produzidas por estações radio base de acesso múltiplo por divisão de código em banda larga - WCDMA

In this work it was developed mathematical resolutions taking as parameter maximum intensity values for the interference analysis of electric and magnetic fields and was given two virtual computer system that supports families of CDMA and WCDMA technologies. The first family were developed computational resources to solve electric and magnetic field calculations and power densities in Radio Base stations , with the use of CDMA technology in the 800 MHz band , taking into account the permissible values referenced by the Commission International Protection on non-Ionizing Radiation . The first family is divided into two segments of calculation carried out in virtual operation. In the first segment to compute the interference field radiated by the base station with input information such as radio channel power; Gain antenna; Radio channel number; Operating frequency; Losses in the cable; Attenuation of direction; Minimum Distance; Reflections. Said computing system allows to quickly and without the need of implementing instruments for measurements, meet the following calculated values: Effective Radiated Power; Sector Power Density; Electric field in the sector; Magnetic field in the sector; Magnetic flux density; point of maximum permissible exposure of electric field and power density. The results are shown in charts for clarity of view of power density in the industry, as well as the coverage area definition. The computer module also includes folders specifications antennas, cables and towers used in cellular telephony, the following manufacturers: RFS World, Andrew, Karthein and BRASILSAT. Many are presented "links" network access "Internet" to supplement the cable specifications, antennas, etc. . In the second segment of the first family work with more variables , seeking to perform calculations quickly and safely assisting in obtaining results of radio signal loss produced by ERB . This module displays screens representing propagation systems denominated "A" and "B". By propagating "A" are obtained radio signal attenuation calculations in areas of urban models , dense urban , suburban , and rural open . In reflection calculations are present the reflection coefficients , the standing wave ratio , return loss , the reflected power ratio , as well as the loss of the signal by mismatch impedance. With the spread " B" seek radio signal losses in the survey line and not targeted , the effective area , the power density , the received power , the coverage radius , the conversion levels and the gain conversion systems radiant . The second family of virtual computing system consists of 7 modules of which 5 are geared towards the design of WCDMA and 2 technology for calculation of telephone traffic serving CDMA and WCDMA . It includes a portfolio of radiant systems used on the site. In the virtual operation of the module 1 is compute-: distance frequency reuse, channel capacity with noise and without noise, Doppler frequency, modulation rate and channel efficiency; Module 2 includes computes the cell area, thermal noise, noise power (dB), noise figure, signal to noise ratio, bit of power (dBm); with the module 3 reaches the calculation: breakpoint, processing gain (dB) loss in the space of BTS, noise power (w), chip period and frequency reuse factor. Module 4 scales effective radiated power, sectorization gain, voice activity and load effect. The module 5 performs the calculation processing gain (Hz / bps) bit time, bit energy (Ws). Module 6 deals with the telephone traffic and scales 1: traffic volume, occupancy intensity, average time of occupancy, traffic intensity, calls completed, congestion. Module 7 deals with two telephone traffic and allows calculating call completion and not completed in HMM. Tests were performed on the mobile network performance field for the calculation of data relating to: CINP , CPI , RSRP , RSRQ , EARFCN , Drop Call , Block Call , Pilot , Data Bler , RSCP , Short Call, Long Call and Data Call ; ECIO - Short Call and Long Call , Data Call Troughput . As survey were conducted surveys of electric and magnetic field in an ERB , trying to observe the degree of exposure to non-ionizing radiation they are exposed to the general public and occupational element. The results were compared to permissible values for health endorsed by the ICNIRP and the CENELEC .

Enjeux éthiques en radiologie diagnostique : comment la bioéthique peut-elle contribuer à une meilleure radioprotection du patient?

Bien que les technologies d’imagerie soient un acquis réel de la médecine moderne, leur introduction ne semble pas avoir été précédée d’une démarche réflexive suffisante qui aurait permis d’anticiper les multiples enjeux que rencontre la pratique radiologique actuelle. En effet, à force de se focaliser sur les acquis techniques et scientifiques, le cadre de radioprotection en place semble ne pas avoir suffisamment considéré l’apport essentiel que représente la connaissance des aspects sociaux, éthiques et humains que peuvent amener des domaines comme la bioéthique. Cette insuffisance fait en sorte que l’on se retrouve aujourd’hui face à des enjeux importants relatifs à la radioprotection du patient comme la surutilisation des examens radiologiques ou encore le manque d’information des acteurs du milieu face aux risques des rayonnements. Après un état des lieux des enjeux éthiques en radiologie diagnostique ayant un impact sur la radioprotection médicale des patients, un enjeu majeur de la pratique actuelle, qui est la justification inadéquate des prescriptions d’examens radiologiques, sera analysé selon une approche par principes. De cet exercice, visant à démontrer comment l’éthique peut concrètement contribuer à la radioprotection, découle l’impératif d’une vision nouvelle et globale permettant de proposer des pistes de solution aux controverses liées à l’utilisation actuelle de l’imagerie. Dans une perspective de santé des populations, il est important de contribuer à la diminution de la banalisation du recours au rayonnement ionisant dans la pratique médicale diagnostique en alliant bioéthique et radioprotection. Ce projet de recherche se veut être une étape limitée, mais nécessaire dans l’établissement de ce dialogue interdisciplinaire.

Recent developments in computed tomography for urolithiasis: diagnosis and characterization.

Objective. To critically evaluate the current literature in an effort to establish the current role of radiologic imaging, advances in computed tomography (CT) and standard film radiography in the diagnosis, and characterization of urinary tract calculi. Conclusion. CT has a valuable role when utilized prudently during surveillance of patients following endourological therapy. In this paper, we outline the basic principles relating to the effects of exposure to ionizing radiation as a result of CT scanning. We discuss the current developments in low-dose CT technology, which have resulted in significant reductions in CT radiation doses (to approximately one-third of what they were a decade ago) while preserving image quality. Finally, we will discuss an important recent development now commercially available on the latest generation of CT scanners, namely, dual energy imaging, which is showing promise in urinary tract imaging as a means of characterizing the composition of urinary tract calculi.

Automated Assessment of Image Quality and Dose Attributes in Clinical CT Images

Computed tomography (CT) is a valuable technology to the healthcare enterprise as evidenced by the more than 70 million CT exams performed every year. As a result, CT has become the largest contributor to population doses amongst all medical imaging modalities that utilize man-made ionizing radiation. Acknowledging the fact that ionizing radiation poses a health risk, there exists the need to strike a balance between diagnostic benefit and radiation dose. Thus, to ensure that CT scanners are optimally used in the clinic, an understanding and characterization of image quality and radiation dose are essential.

The state-of-the-art in both image quality characterization and radiation dose estimation in CT are dependent on phantom based measurements reflective of systems and protocols. For image quality characterization, measurements are performed on inserts imbedded in static phantoms and the results are ascribed to clinical CT images. However, the key objective for image quality assessment should be its quantification in clinical images; that is the only characterization of image quality that clinically matters as it is most directly related to the actual quality of clinical images. Moreover, for dose estimation, phantom based dose metrics, such as CT dose index (CTDI) and size specific dose estimates (SSDE), are measured by the scanner and referenced as an indicator for radiation exposure. However, CTDI and SSDE are surrogates for dose, rather than dose per-se.

Currently there are several software packages that track the CTDI and SSDE associated with individual CT examinations. This is primarily the result of two causes. The first is due to bureaucracies and governments pressuring clinics and hospitals to monitor the radiation exposure to individuals in our society. The second is due to the personal concerns of patients who are curious about the health risks associated with the ionizing radiation exposure they receive as a result of their diagnostic procedures.

An idea that resonates with clinical imaging physicists is that patients come to the clinic to acquire quality images so they can receive a proper diagnosis, not to be exposed to ionizing radiation. Thus, while it is important to monitor the dose to patients undergoing CT examinations, it is equally, if not more important to monitor the image quality of the clinical images generated by the CT scanners throughout the hospital.

The purposes of the work presented in this thesis are threefold: (1) to develop and validate a fully automated technique to measure spatial resolution in clinical CT images, (2) to develop and validate a fully automated technique to measure image contrast in clinical CT images, and (3) to develop a fully automated technique to estimate radiation dose (not surrogates for dose) from a variety of clinical CT protocols.

Molecular Mechanisms of Airway Epithelial Progenitor Cell Maintenance and Repair.

The lungs are vital organs whose airways are lined with a continuous layer of epithelial cells. Epithelial cells in the distal most part of the lung, the alveolar space, are specialized to facilitate gas exchange. Proximal to the alveoli is the airway epithelium, which provides an essential barrier and is the first line of defense against inhaled toxicants, pollutants, and pathogens. Although the postnatal lung is a quiescent organ, it has an inherent ability to regenerate in response to injury. Proper balance between maintaining quiescence and undergoing repair is crucial, with imbalances in these processes leading to fibrosis or tumor development. Stem and progenitor cells are central to maintaining balance, given that they proliferate and renew both themselves and the various differentiated cells of the lung. However, the precise mechanisms regulating quiescence and repair in the lungs are largely unknown. In this dissertation, ionizing radiation is used as a physiologically relevant injury model to better understand the repair process of the airway epithelium. We use in vitro and in vivo mouse models to study the response of a secretory progenitor, the club cell, to various doses and qualities of ionizing radiation. Exposure to radiation found in space environments and in some types of radiotherapy caused clonal expansion of club cells specifically in the most distal branches of the airway epithelium, indicating that the progenitors residing in the terminal bronchioles are radiosensitive. This clonal expansion is due to an increase in p53-dependent apoptosis, senescence, and mitotic defects. Through the course of this work, we discovered that p53 is not only involved in radiation response, but is also a novel regulator of airway epithelial homeostasis. p53 acts in a gene dose-dependent manner to regulate the composition of airway epithelium by maintaining quiescence and regulating differentiation of club progenitor cells in the steady-state lung. The work presented in this dissertation represents an advance in our understanding of the molecular mechanisms underlying maintenance of airway epithelial progenitor cells as well as their repair following ionizing radiation exposure.

Functional analysis of the ATM-p53-p21 pathway in the LRF CLL4 trial: blockade at the level of p21 is associated with short response duration.

PURPOSE: This study sought to establish whether functional analysis of the ATM-p53-p21 pathway adds to the information provided by currently available prognostic factors in patients with chronic lymphocytic leukemia (CLL) requiring frontline chemotherapy. EXPERIMENTAL DESIGN: Cryopreserved blood mononuclear cells from 278 patients entering the LRF CLL4 trial comparing chlorambucil, fludarabine, and fludarabine plus cyclophosphamide were analyzed for ATM-p53-p21 pathway defects using an ex vivo functional assay that uses ionizing radiation to activate ATM and flow cytometry to measure upregulation of p53 and p21 proteins. Clinical endpoints were compared between groups of patients defined by their pathway status. RESULTS: ATM-p53-p21 pathway defects of four different types (A, B, C, and D) were identified in 194 of 278 (70%) samples. The type A defect (high constitutive p53 expression combined with impaired p21 upregulation) and the type C defect (impaired p21 upregulation despite an intact p53 response) were each associated with short progression-free survival. The type A defect was associated with chemoresistance, whereas the type C defect was associated with early relapse. As expected, the type A defect was strongly associated with TP53 deletion/mutation. In contrast, the type C defect was not associated with any of the other prognostic factors examined, including TP53/ATM deletion, TP53 mutation, and IGHV mutational status. Detection of the type C defect added to the prognostic information provided by TP53/ATM deletion, TP53 mutation, and IGHV status. CONCLUSION: Our findings implicate blockade of the ATM-p53-p21 pathway at the level of p21 as a hitherto unrecognized determinant of early disease recurrence following successful cytoreduction.

Heating the Early Universe : Numerical Methods and Their Analysis

During the epoch when the first collapsed structures formed (6<z<50) our Universe went through an extended period of changes. Some of the radiation from the first stars and accreting black holes in those structures escaped and changed the state of the Intergalactic Medium (IGM). The era of this global phase change in which the state of the IGM was transformed from cold and neutral to warm and ionized, is called the Epoch of Reionization.In this thesis we focus on numerical methods to calculate the effects of this escaping radiation. We start by considering the performance of the cosmological radiative transfer code C2-Ray. We find that although this code efficiently and accurately solves for the changes in the ionized fractions, it can yield inaccurate results for the temperature changes. We introduce two new elements to improve the code. The first element, an adaptive time step algorithm, quickly determines an optimal time step by only considering the computational cells relevant for this determination. The second element, asynchronous evolution, allows different cells to evolve with different time steps. An important constituent of methods to calculate the effects of ionizing radiation is the transport of photons through the computational domain or ``ray-tracing''. We devise a novel ray tracing method called PYRAMID which uses a new geometry - the pyramidal geometry. This geometry shares properties with both the standard Cartesian and spherical geometries. This makes it on the one hand easy to use in conjunction with a Cartesian grid and on the other hand ideally suited to trace radiation from a radially emitting source. A time-dependent photoionization calculation not only requires tracing the path of photons but also solving the coupled set of photoionization and thermal equations. Several different solvers for these equations are in use in cosmological radiative transfer codes. We conduct a detailed and quantitative comparison of four different standard solvers in which we evaluate how their accuracy depends on the choice of the time step. This comparison shows that their performance can be characterized by two simple parameters and that the C2-Ray generally performs best.

Evaluation of Transport Properties of Nanofiltration Membranes Exposed to Radioactive Liquid Waste

The application of membrane separation processes (PSM) for treatment of radioactive waste requires the selection of a suitable membrane for the treatment of waste, as the membrane will be directly exposed to the radioactive liquid waste, and also exposed to ionizing radiation. The nanofiltration membrane is most suitable for treatment of radioactive waste, since it has high rejection of multivalent ions. Usually the membranes are made of polymers and depending on the composition of the waste, type and dose of radiation absorbed may be changes in the structure of the membrane, resulting in loss of its transport properties. We tested two commercial nanofiltration membranes: NF and SW Dow/Filmtec. The waste liquid used was obtained in the process of conversion of uranium hexafluoride gas to solid uranium dioxide, known as "carbonated water". The membranes were characterized as their transport properties (hydraulic permeability, permeate flux and salt rejection) before and after their immersion in the waste for 24 hours. The surface of the membranes was also evaluated by SEM and FTIR. It was observed that in both the porosity of the membrane selective layer was altered, but not the membrane surface charge, which is responsible for the selectivity of the membrane. The NF membranes and SW showed uranium ion rejection of 64% and 55% respectively.

Suivi par élastographie ultrasonore après réparation endovasculaire d’anévrisme aorto-iliaque : étude de faisabilité in vivo

Les maladies cardiovasculaires sont la première cause de mortalité dans le monde et les anévrismes de l’aorte abdominale (AAAs) font partie de ce lot déplorable. Un anévrisme est la dilatation d’une artère pouvant conduire à la mort. Une rupture d’AAA s’avère fatale près de 80% du temps. Un moyen de traiter les AAAs est l’insertion d’une endoprothèse (SG) dans l’aorte, communément appelée la réparation endovasculaire (EVAR), afin de réduire la pression exercée par le flux sanguin sur la paroi. L’efficacité de ce traitement est compromise par la survenue d’endofuites (flux sanguins entre la prothèse et le sac anévrismal) pouvant conduire à la rupture de l’anévrisme. Ces flux sanguins peuvent survenir à n’importe quel moment après le traitement EVAR. Une surveillance par tomodensitométrie (CT-scan) annuelle est donc requise, augmentant ainsi le coût du suivi post-EVAR et exposant le patient à la radiation ionisante et aux complications des contrastes iodés. L’endotension est le concept de dilatation de l’anévrisme sans la présence d’une endofuite apparente au CT-scan. Après le traitement EVAR, le sang dans le sac anévrismal coagule pour former un thrombus frais, qui deviendra progressivement un thrombus plus fibreux et plus organisé, donnant lieu à un rétrécissement de l’anévrisme. Il y a très peu de données dans la littérature pour étudier ce processus temporel et la relation entre le thrombus frais et l’endotension. L’étalon d’or du suivi post-EVAR, le CT-scan, ne peut pas détecter la présence de thrombus frais. Il y a donc un besoin d’investir dans une technique sécuritaire et moins coûteuse pour le suivi d’AAAs après EVAR. Une méthode récente, l’élastographie dynamique, mesure l’élasticité des tissus en temps réel. Le principe de cette technique repose sur la génération d’ondes de cisaillement et l’étude de leur propagation afin de remonter aux propriétés mécaniques du milieu étudié. Cette thèse vise l’application de l’élastographie dynamique pour la détection des endofuites ainsi que de la caractérisation mécanique des tissus du sac anévrismal après le traitement EVAR. Ce projet dévoile le potentiel de l’élastographie afin de réduire les dangers de la radiation, de l’utilisation d’agent de contraste ainsi que des coûts du post-EVAR des AAAs. L’élastographie dynamique utilisant le « Shear Wave Imaging » (SWI) est prometteuse. Cette modalité pourrait complémenter l’échographie-Doppler (DUS) déjà utilisée pour le suivi d’examen post-EVAR. Le SWI a le potentiel de fournir des informations sur l’organisation fibreuse du thrombus ainsi que sur la détection d’endofuites. Tout d’abord, le premier objectif de cette thèse consistait à tester le SWI sur des AAAs dans des modèles canins pour la détection d’endofuites et la caractérisation du thrombus. Des SGs furent implantées dans un groupe de 18 chiens avec un anévrisme créé au moyen de la veine jugulaire. 4 anévrismes avaient une endofuite de type I, 13 avaient une endofuite de type II et un anévrisme n’avait pas d’endofuite. Des examens échographiques, DUS et SWI ont été réalisés à l’implantation, puis 1 semaine, 1 mois, 3 mois et 6 mois après le traitement EVAR. Une angiographie, un CT-scan et des coupes macroscopiques ont été produits au sacrifice. Les régions d’endofuites, de thrombus frais et de thrombus organisé furent identifiées et segmentées. Les valeurs de rigidité données par le SWI des différentes régions furent comparées. Celles-ci furent différentes de façon significative (P < 0.001). Également, le SWI a pu détecter la présence d’endofuites où le CT-scan (1) et le DUS (3) ont échoué. Dans la continuité de ces travaux, le deuxième objectif de ce projet fut de caractériser l’évolution du thrombus dans le temps, de même que l’évolution des endofuites après embolisation dans des modèles canins. Dix-huit anévrismes furent créés dans les artères iliaques de neuf modèles canins, suivis d’une endofuite de type I après EVAR. Deux gels embolisants (Chitosan (Chi) ou Chitosan-Sodium-Tetradecyl-Sulfate (Chi-STS)) furent injectés dans le sac anévrismal pour promouvoir la guérison. Des examens échographiques, DUS et SWI ont été effectués à l’implantation et après 1 semaine, 1 mois, 3 mois et 6 mois. Une angiographie, un CT-scan et un examen histologique ont été réalisés au sacrifice afin d’évaluer la présence, le type et la grosseur de l’endofuite. Les valeurs du module d’élasticité des régions d’intérêts ont été identifiées et segmentées sur les données pathologiques. Les régions d’endofuites et de thrombus frais furent différentes de façon significative comparativement aux autres régions (P < 0.001). Les valeurs d’élasticité du thrombus frais à 1 semaine et à 3 mois indiquent que le SWI peut évaluer la maturation du thrombus, de même que caractériser l’évolution et la dégradation des gels embolisants dans le temps. Le SWI a pu détecter des endofuites où le DUS a échoué (2) et, contrairement au CT-scan, détecter la présence de thrombus frais. Finalement, la dernière étape du projet doctoral consistait à appliquer le SWI dans une phase clinique, avec des patients humains ayant déjà un AAA, pour la détection d’endofuite et la caractérisation de l’élasticité des tissus. 25 patients furent sélectionnés pour participer à l’étude. Une comparaison d’imagerie a été produite entre le SWI, le CT-scan et le DUS. Les valeurs de rigidité données par le SWI des différentes régions (endofuite, thrombus) furent identifiées et segmentées. Celles-ci étaient distinctes de façon significative (P < 0.001). Le SWI a détecté 5 endofuites sur 6 (sensibilité de 83.3%) et a eu 6 faux positifs (spécificité de 76%). Le SWI a pu détecter la présence d’endofuites où le CT-scan (2) ainsi que le DUS (2) ont échoué. Il n’y avait pas de différence statistique notable entre la rigidité du thrombus pour un AAA avec endofuite et un AAA sans endofuite. Aucune corrélation n’a pu être établie de façon significative entre les diamètres des AAAs ainsi que leurs variations et l’élasticité du thrombus. Le SWI a le potentiel de détecter les endofuites et caractériser le thrombus selon leurs propriétés mécaniques. Cette technique pourrait être combinée au suivi des AAAs post-EVAR, complémentant ainsi l’imagerie DUS et réduisant le coût et l’exposition à la radiation ionisante et aux agents de contrastes néphrotoxiques.