Radiogenomics in gynecological cancer patients

Radiotherapie wordt toegepast bij ongeveer de helft van alle kankerpatiënten en vormt bijgevolg één van de belangrijkste behandelingsmethoden tegen kanker. Niettegenstaande de bestralingstechnieken de laatste jaren veel verbeterd zijn, treedt schade aan normale weefsels nog steeds op. Bovendien variëren deze stralingsgeïnduceerde complicaties sterk van patiënt tot patiënt. Door de stijgende overlevingsgraad van kankerpatiënten is de preventie of reductie van late neveneffecten ten gevolge van radiotherapie een prioriteit geworden. Met een in vitro test die de individuele radiosensitiviteit kan voorspellen vóór de radiotherapiebehandeling, zouden de behandelingsschema’s verder kunnen aangepast worden zodat stralingsgeïnduceerde toxiciteit aan normale weesfels tot een absoluut minimum beperkt wordt. Gynaecologische tumoren maken een groot deel uit van het aantal kankers in vrouwen over de hele wereld. De meeste van deze maligniteiten, in het bijzonder cervix- en endometriumkanker, worden operatief behandeld gevolgd door radiotherapie. Voor deze thesis werd een patiëntengroep bestaande uit vrouwen behandeld voor cervix- of endometriumkanker opgevolgd voor late stralingstoxiciteit. De laatste 10-tallen jaren werden verschillende in vitro testen ontwikkeld teneinde schade aan normale weefsels ten gevolge van radiotherapie te voorspellen. In het eerste deel van deze thesis werd de toepasbaarheid nagegaan van de cytogenetische G2 test op perifere bloedlymfocyten als biomerker voor late klinische radiosensitiviteit. Er kon aangetoond worden dat het gemiddeld aantal chromatidbreuken per cel significant hoger is in patiënten met late normale weefselreacties dan in patiënten zonder deze reacties. De G2 test miste echter sensitiviteit om individuele patiënten met een verhoogd risico te identificeren. Bijgevolg heeft de G2 test een beperkte bruikbaarheid bij de klinische screening voor individuele radiosensitiviteit. Momenteel wordt radiosensitiviteit van normale weefsels beschouwd als een overerfbare complexe aandoening die bepaald wordt door de interactie tussen verschillende genen of genproducten. Er wordt bijgevolg verondersteld dat klinische radiosensitiviteit voorspeld kan worden van individuele genetische profielen. DNA herstel is één van de belangrijkste mechanismen van cellen en weefsels als respons op straling. Daarom werd de associatie bestudeerd tussen acht single nucleotide polymorfismen (SNPs) in de DNA herstelgenen XRCC1, XRCC3 en OGG1 en de ontwikkeling van laattijdige radiotherapiereacties. De selectie van deze SNPs was gebaseerd op literatuurdata betreffende de mogelijke betrokkenheid van deze SNPs in kankerpredispositie en radiosensitiviteit. In dit werk werd aangetoond dat het XRCC3 IVS5-14 polymorfisme significant geassocieerd is met het risico op de ontwikkeling van laattijdige radiotherapiereacties. De overige individuele SNPs konden echter niet geassocieerd worden met een verhoogde stralingstoxiciteit. Klinische radiosensitiviteit bleek wel significant geassocieerd met een combinatie van verschillende SNPs in XRCC1 en XRCC3 op basis van een risico-allel analyse. In het tweede deel van deze thesis werd de betrokkenheid bestudeerd van drie microsatelliet polymorfismen in de DNA herstelgenen XRCC1, XRCC3 en XRCC5 bij late klinische radiosensitiviteit. Deze studie werd uitgevoerd uitgaande van veelbelovende literatuurdata die wijzen op de associatie tussen klinische radiosensitiviteit en zeldzame microsatellieten. Hoewel geen significante associatie gevonden werd tussen de lengte van één van de microsatellieten en het voorkomen van laattijdige radiotherapiereacties, kon de mogelijke betrokkenheid van korte en lange XRCC1 herhalingen niet uitgesloten worden. De laatste jaren is het duidelijk geworden dat radiosensitiviteit van normale weefsels niet enkel veroorzaakt wordt door celdood, maar het resultaat is van multicellulaire interacties tussen verscheidene celtypes in een specifiek weefsel of orgaan. De vroege activatie van cytokine cascades na stralingsblootstelling heeft een grote invloed op de respons van normale weefsels. Het profibrotische cytokine TGFβ1 speelt een cruciale rol in de ontwikkeling van stralingsgeïnduceerde late weefselreacties. Bijgevolg werd in het laatste deel van deze thesis de associatie nagegaan tussen zes polymorfismen in TGFβ1 en het voorkomen van late toxiciteit van normale weefsels. Deze studie toonde aan dat het -1.552delAGG, het -509C>T en het Leu10Pro polymorfisme sterk met elkaar geassocieerd zijn, en dat het risico op late stralingstoxiciteit gemoduleerd kan worden door deze polymorfismen. De studies uitgevoerd in deze thesis hebben bijgedragen tot het lopende onderzoek met als doel genetische profielen te identificeren die geassocieerd zijn met radiosensitiviteit van normale weefsels. Er werden indicaties gegeven dat polymorfismen in de XRCC1 en XRCC3 DNA herstelgenen en in het cytokine TGFβ1 betrokken kunnen zijn in de ontwikkeling van late radiotherapiereacties. Gelijkaardige associaties voor de TGFβ1 SNPs werden ook reeds gerapporteerd in andere onafhankelijke studies. Dit ondersteunt de mogelijke betrokkenheid van deze TGFβ1 SNPs in laattijdige radiotherapiereacties. Om tot een volledig begrip van de genetische basis van klinische radiosensitiviteit te komen en om genetische data aan te wenden in de screening naar klinische radiosensitiviteit, zijn echter grootschalige studies noodzakelijk die gebruik maken van high-troughput technologieën in een multicenter setting

Performance, Gaseous and Particle Emissions from a Residential Pellet Stove

The objectives of this chapter are to present experimental results on performance, gaseous and particle emissions obtained from a modern bottom feed pellet stove of 2.5 kW output in part load heat and 5 kW output in nominal heat. Two experiments in part load and four experiments in nominal load output were conducted in a stove manufacturing plant in the southern part of Belgium. The particle emissions measurements are mass concentrations of PM1 and PM2.5, number concentrations and their particle size distributions. Particle emission measurements were conducted continuously from a partial flow dilution tunnel using an Electrical Low Pressure Impactor Plus (ELPI+). The CO emissions were analyzed continuously from the flue gas by a Siemens Ultramat 6 gas analyzer, CO2 and O2 concentrations were measured continuously using a Horiba PG-250 gas analyzer. A performance analysis in terms of combustion efficiency together with different losses of the pellet stove is also discussed. The results show that PM1 and PM2.5 concentrations obtained from the combustion phase of the nominal load experiments varied from 43.3 to 276 mg/Nm3 and 66 to 36 mg/Nm3 respectively, while the particle number concentrations varied from 1.4 × 107 to 8.8 × 107 particles/cm3. The CO emissions obtained from the main combustion phase of the nominal load heat varied output from 50 to 145 mg/Nm3

Management of the Belgian coast: opinions and solutions

Since the beginning of the 20th century the Belgian coast has undergone important changes of which an overview is presented here. To determine the view of the Belgian public on the Belgian coast and in order to obtain their opinions and solutions to the problems along the Belgian coast, a questionnaire survey was conducted with a total of 100 respondents divided into five groups, all active in the coastal zone. The five groups included (1) politicians on various levels of authority, (2) coastal entrepreneurs and business people, (3) naturalists and scientists, (4) coastal residents and (5) tourists. Coastal zone problems, as perceived by the different groups, and their solutions are discussed. Former municipalities, in particular, were held responsible for the current coastal problems. Most respondents were skeptic about the application of recent juridical instruments (e.g. the Dune Decree), the structural plans and their power to protect the remaining natural areas. The root of the problems seems to lie in lack of coordination and communication between different authorities responsible for the coastal zone

Tetartohedral twinning in IDI-2 from Thermus thermophilus: crystallization under anaerobic conditions

pre-printType-2 isopentenyl diphosphate isomerase (IDI-2) is a key flavoprotein involved in the biosynthesis of isoprenoids. Since fully reduced flavin mononucleotide (FMNH2) is needed for activity, it was decided to crystallize the enzyme under anaerobic conditions in order to understand how this reduced cofactor binds within the active site and interacts with the substrate isopentenyl diphosphate (IPP). In this study, the protein was expressed and purified under aerobic conditions and then reduced and crystallized under anaerobic conditions. Crystals grown by the sitting-drop vapour-diffusion method and then soaked with IPP diffracted to 2.1 Å resolution and belonged to the hexagonal space group P6322, with unit-cell parameters a = b = 133.3, c = 172.9 Å

Investigation on Gaseous and Particle Mass Emissions from Automatically Fired Small Scale Heating System under Laboratory Conditions

This study presents the experimental results on gaseous and particle mass emissions obtained from a bottom feed pellet stove of 2.5 kW output in part load heat and 5 kW output in nominal heat. The experiments were conducted in a stove manufacturing plant in the southern part of Belgium. Two combustion experiments (A and B) in part load heat output and four experiments (C, D, E and E) in nominal load were performed at three combustion phases: startup, combustion and burnout phase. The pellet stove was operated in different fan speeds varied from 900 rpm to 1250 rpm for the combustion experiments. Experiments A and B were operated with low speed fan, C and D with medium speed fan, E and F with high speed fan. The emissions results include CO2, CO, O2 and particle mass concentrations are presented in this study. A performance analysis in terms of combustion efficiency together with different losses of the pellet stove is also discussed. The experimental results show that CO emissions obtained from the main combustion phase of the part load heat output experiments varied from 1215 mg/Nm3 to 1450 mg/Nm3, while in the nominal load heat output varied from 50 mg/Nm3 to 145 mg/Nm3. Also, the results show that CO emissions in the burnout phase from all the experiments were significantly higher than that in the startup phase followed by the combustion phase. The finding shows that higher CO emissions in the startup and burnout phase have influence on the total CO emissions. Particle mass emissions obtained from the combustion experiments operated with high fan speed varied from 10-15 mg/Nm3 respectively and were much lower than the required limit value of standard EN14785 and other works. The combustion efficiency obtained from all the experiments for the low speed fan, medium speed fan and high speed fan was 92.8±1.2 %, 92.4±1.1 % and 92.7±1.2 % respectively and satisfied the required limit value of the standard. Article History: Received Sept 12th 2017; Received in revised form March 17th 2018; Accepted April 26th 2018; Available online How to Cite This Article: Obaidullah, M., Bram, S. and De Ruyck, J. (2018) Investigation on Gaseous and Particle Mass Emissions from Automatically Fired Small Scale Heating System under Laboratory Conditions. Int. Journal of Renewable Energi Development, 7(2), 111-121. https://doi.org/10.14710/ijred.7.2.111-12

Factors modifying the risk for developing acute skin toxicity after whole-breast intensity modulated radiotherapy

Background: After breast-conserving radiation therapy most patients experience acute skin toxicity to some degree. This may impair patients' quality of life, cause pain and discomfort. In this study, we investigated treatment and patient-related factors, including genetic polymorphisms, that can modify the risk for severe radiation-induced skin toxicity in breast cancer patients. Methods: We studied 377 patients treated at Ghent University Hospital and at ST.-Elisabeth Clinic and Maternity in Namur, with adjuvant intensity modulated radiotherapy (IMRT) after breast-conserving surgery for breast cancer. Women were treated in a prone or supine position with normofractionated (25 x 2 Gy) or hypofractionated (15 x 2.67 Gy) IMRT alone or in combination with other adjuvant therapies. Patient-and treatment-related factors and genetic markers in regulatory regions of radioresponsive genes and in LIG3, MLH1 and XRCC3 genes were considered as variables. Acute dermatitis was scored using the CTCAEv3.0 scoring system. Desquamation was scored separately on a 3-point scale (0-none, 1-dry, 2-moist). Results: Two-hundred and twenty patients (58%) developed G2+ dermatitis whereas moist desquamation occurred in 56 patients (15%). Normofractionation (both p = D (p = 0.001 and p = 0.043) and concurrent hormone therapy (p = 0.001 and p = 0.037) were significantly associated with occurrence of acute dermatitis and moist desquamation, respectively. Additional factors associated with an increased risk of acute dermatitis were the genetic variation in MLH1 rs1800734 (p=0.008), smoking during RT (p = 0.010) and supine IMRT (p = 0.004). Patients receiving trastuzumab showed decreased risk of acute dermatitis (p < 0.001). Conclusions: The normofractionation schedule, supine IMRT, concomitant hormone treatment and patient related factors (high BMI, large breast, smoking during treatment and the genetic variation in MLH1 rs1800734) were associated with increased acute skin toxicity in patients receiving radiation therapy after breast-conserving surgery. Trastuzumab seemed to be protective

Mycotoxin exposure assessments in a multi-center European validation study by 24-hour dietary recall and biological fluid sampling

The European Food Consumption Validation (EFCOVAL) project includes 600 men and women from Belgium, the Czech Republic, France, the Netherlands, and Norway, who had given serum and 24-hour urine samples, and completed 24-hour dietary recall (24-HDR) interviews. Consumption, according to 24-HDR, was matched against the European Food Safety Authority (EFSA) databases of mycotoxin contaminations, via the FoodEx1 standard classifications, producing an indirect external estimate of dietary mycotoxin exposure. Direct, internal measurements of dietary mycotoxin exposure were made in serum and urine by ultra-performance liquid chromatography coupled to tandem mass spectrometry. For the first time, mycotoxin exposures were thoroughly compared between two 24-HDRs, and two 24-hour urine samples collected during the same days covered by the 24-HDRs. These measurements were compared to a single-time point serum measurement to investigate evidence of chronic mycotoxin exposure. According to 24-HDR data, all 600 individuals were exposed to between 4 and 34 mycotoxins, whereof 10 found to exceed the tolerable daily intake. Correlations were observed between two time points, and significant correlations were observed between concentrations in serum and urine. However, only acetyldeoxynivalenol, ochratoxin A, and sterigmatocystin were found to have significant positive correlations between 24-HDR exposures and serum, while aflatoxin G1 and G2, HT-2 toxin, and deoxynivalenol were associated between concurrent 24-HDR and 24-hour urine. Substantial agreements on quantitative levels between serum and urine were observed for the groups Type B Trichothecenes and Zearalenone. Further research is required to bridge the interpretation of external and internal exposure estimates of the individual on a time scale of hours. Additionally, metabolomic profiling of dietary mycotoxin exposures could help with a comprehensive assessment of single time-point exposures, but also with the identification of chronic exposure biomarkers. Such detailed characterization informs population exposure assessments, and aids in the interpretation of epidemiological health outcomes related to multi-mycotoxin exposure

Prototyping for non-designers : reflecting on the use of interactive prototyping tools

Scientists and designers show different problem-solving strategies. Where scientists generally adopt a strategy of analysis; designers are more inclined to solve a problem by synthesis. Instead of striving for a deep understanding and analysis of the problem, a designer tackles a problem by quickly generating a satisfactory solution. Prototyping is one of the tools for designers to conceptualise and realise new product solutions. Fifteen students in their final year at the university following Political and Communication Sciences received an introduction to the programs Makey Makey and Scratch. All participants had little to no experience with programming and prototyping. The reflections on the workshop are described from a teacher and students' point of view through qualitative interviews and a post survey. Results shine a light on the level of enjoyment, satisfaction and barriers of the students about the new learned tools. We conclude that interactive prototyping for non-designers is valuable and other non-design disciplines can quickly integrate such tools