Microsatellite polymorphisms in DNA repair genes XRCC1, XRCC3 and XRCC5 in patients with gynecological tumors: Association with late clinical radiosensitivity and cancer incidence

This study investigates the association of microsatellite polymorphisms in XRCC1, XRCC3 and XRCC5 with the development of late radiation-induced radiotherapy reactions and examines the correlation between these microsatellites and cancer incidence. Sixty-two women with cervical or endometrial cancer treated with radiotherapy were included in the study. According to the CTCAEv3.0 scale, 22 patients showed late adverse radiotherapy reactions (grade 2 or more). PCR on lymphocyte DNA followed by automated fragment analysis was performed to examine the number of tandem repeat units at each locus. No significant association was found between the repeat length at any of the microsatellites in XRCC1, XRCC3 or XRCC5 and the incidence of late radiotherapy complications. Since higher odds ratios (ORs) were found for the rare XRCC1 [AC]11 and [AC]21 repeats (OR = 2.65, P = 0.325 and OR = 8.67, P = 0.093, respectively), the possible involvement of these small and large repeats in clinical radiosensitivity cannot be completely ruled out. When specific numbers of repeats were examined, no significant correlation was found between the microsatellite repeat length in XRCC1 and XRCC5 and cancer incidence. A weak correlation between XRCC3 [AC]16 homozygotes and cancer incidence was found (OR = 2.56, P = 0.055). A large-scale multicenter study of cancer patients with a high number of radiosensitive individuals is needed to clarify the value of rare polymorphic microsatellite repeats in XRCC1 and XRCC3 as a biomarker of clinical radiosensitivity or increased cancer risk

Exploring Decisions to Undertake a Marathon and Adherence Challenges in a Novice Runner With Parkinson

Evidence endorses the benefits of more vigorous exercise for people with Parkinson’s, particularly following diagnosis, yet is not clear which style is optimal. The authors share perspectives and decisions made as a physiotherapist (assisted by a sports and exercise science student) and a novice runner with Parkinson’s in his late 50s, respectively. The exercise goal chosen by the runner (the case report participant) to minimize the degenerative effects of the progressive condition was to complete a marathon. Methods: This coauthored report evaluates the participant’s progress utilizing physical fitness assessment data plus reflections on his training regime and notes from training diaries for the year before and after the marathon. Results: The participant received nutritional advice for weight management as exercise increased and physiotherapy for injuries from mounting activity level on Parkinsonian muscle tone. Fitness and function improved or were maintained (leg power, flexibility, timed functional walking, and balance). Most, however, returned to baseline within 6 months following the marathon as training intensity dropped. Conclusions: Physical function can be improved or maintained in individuals with neurodegenerative conditions with correct exercise and nutritional advice. The participant’s choice of running was based on recommendations for condition maintenance and not enjoyment, so adherence and completion of the marathon goal required professional, family, and technological support

Chromosomal radiosensitivity in head and neck cancer patients: evidence for genetic predisposition?

The association between chromosomal radiosensitivity and genetic predisposition to head and neck cancer was investigated in this study. In all, 101 head and neck cancer patients and 75 healthy control individuals were included in the study. The G2 assay was used to measure chromosomal radiosensitivity. The results demonstrated that head and neck cancer patients had a statistically higher number of radiation-induced chromatid breaks than controls, with mean values of 1.23 and 1.10 breaks per cell, respectively (P<0.001). Using the 90th percentile of the G2 scores of the healthy individuals as a cutoff value for chromosomal radiosensitivity, 26% of the cancer patients were radiosensitive compared with 9% of the healthy controls (P=0.008). The mean number of radiation-induced chromatid breaks and the proportion of radiosensitive individuals were highest for oral cavity cancer patients (1.26 breaks per cell, 38%) and pharynx cancer patients (1.27 breaks per cell, 35%). The difference between patients and controls was most pronounced in the lower age group (⩽50 years, 1.32 breaks per cell, 38%) and in the non- and light smoking patient group (⩽10 pack-years, 1.28 breaks per cell, 46%). In conclusion, enhanced chromosomal radiosensitivity is a marker of genetic predisposition to head and neck cancer, and the genetic contribution is highest for oral cavity and pharynx cancer patients and for early onset and non- and light smoking patients

REQUITE: A prospective multicentre cohort study of patients undergoing radiotherapy for breast, lung or prostate cancer

Purpose: REQUITE aimed to establish a resource for multi-national validation of models and biomarkers that predict risk of late toxicity following radiotherapy. The purpose of this article is to provide summary descriptive data. Methods: An international, prospective cohort study recruited cancer patients in 26 hospitals in eight countries between April 2014 and March 2017. Target recruitment was 5300 patients. Eligible patients had breast, prostate or lung cancer and planned potentially curable radiotherapy. Radiotherapy was prescribed according to local regimens, but centres used standardised data collection forms. Pre-treatment blood samples were collected. Patients were followed for a minimum of 12 (lung) or 24 (breast/prostate) months and summary descriptive statistics were generated. Results: The study recruited 2069 breast (99% of target), 1808 prostate (86%) and 561 lung (51%) cancer patients. The centralised, accessible database includes: physician-(47,025 forms) and patient-(54,901) reported outcomes; 11,563 breast photos; 17,107 DICOMs and 12,684 DVHs. Imputed genotype data are available for 4223 patients with European ancestry (1948 breast, 1728 prostate, 547 lung). Radiation-induced lymphocyte apoptosis (RILA) assay data are available for 1319 patients. DNA (n = 4409) and PAXgene tubes (n = 3039) are stored in the centralised biobank. Example prevalences of 2-year (1-year for lung) grade >= 2 CTCAE toxicities are 13% atrophy (breast), 3% rectal bleeding (prostate) and 27% dyspnoea (lung). Conclusion: The comprehensive centralised database and linked biobank is a valuable resource for the radiotherapy community for validating predictive models and biomarkers. Patient summary: Up to half of cancer patients undergo radiation therapy and irradiation of surrounding healthy tissue is unavoidable. Damage to healthy tissue can affect short-and long-term quality-of-life. Not all patients are equally sensitive to radiation "damage" but it is not possible at the moment to identify those who are. REQUITE was established with the aim of trying to understand more about how we could predict radiation sensitivity. The purpose of this paper is to provide an overview and summary of the data and material available. In the REQUITE study 4400 breast, prostate and lung cancer patients filled out questionnaires and donated blood. A large amount of data was collected in the same way. With all these data and samples a database and biobank were created that showed it is possible to collect this kind of information in a standardised way across countries. In the future, our database and linked biobank will be a resource for research and validation of clinical predictors and models of radiation sensitivity. REQUITE will also enable a better understanding of how many people suffer with radiotherapy toxicity

Toxicokinetiek van oraal toegediend lindaan (y-HCH) en diverse PCB-congeneren in de geit

Practical use of the results of this report in report 643810005In 1995 is door Olling et al. een methode geintroduceerd om in landbouwhuisdieren te schatten wat de huidige lichaamsbelasting en de dagelijkse opname van een milieucontaminant in het recente verleden is geweest. Deze methode is gebaseerd op slechts enkele metingen in melk, bloed of vet. Het doel van de in dit rapport beschreven studie is deze methode van monstername te valideren en vervolgens hieruit een rekenmodule plus een Graphical User Interface (GUI) te ontwikkelen (zie ook RIVM-rapportnummer 643810005). Ter validatie van de methode is een experiment opgezet waarbij aan geiten hetzij PCBs, hetzij lindaan (y-HCH) is toegediend. Om de kinetiek van de afzondelijke PCBs en lindaan te beschrijven is een PBPK model voor de geit opgesteld. De geschatte standaard fysiologische parameters en de gevonden parameters zijn geomplementeerd in een schattingsmodule. Een deel van de data is vervolgens gebruikt om huidige lichaamsbelasting en dagelijkse absorptie in de geit te schatten. Het blijkt dat de methode goed gebruikt zou kunnen worden als een eerste test om inzicht te krijgen in de contaminatie van een bedrijf.In 1995 Olling et al. proposed a method to assess the body burden and daily absorption of a lipophilic contaminant in cattle both prospectively and retrospectively on the basis of only a limited number of measurements in milk, blood or fat. In order to validate the applicability of this method, it was decided to assess its performance by means of an experiment in goats who would receive known amounts of PCB congeners or lindane (y-HCH). Subsequently, contaminant concentrations in plasma and milkfat were measured. These results were incorporated into a PBPK model of the goat in order to describe the kinetics of the individual PCB congeners and lindane. Estimation of kinetic parameters was carried out by fitting them to the data in an automated procedure. The estimated standard physiological parameters of the goat together with the fitted kinetic parameter values have been implemented into an estimation module based on the assessment method. Part of the data has been used to estimate the known body burden and daily absorption. It appears that the method offers a good screening tool for gaining insight into current body burden and recent history of contamination of cattle.Inspectie W en

Toepassing van de postimplantatie rattenembryokweek voor interne dosis modellering bij de risicoevaluatie van embryotoxiciteit

De bruikbaarheid van de postimplantatie embryokweek voor interne dosis-modellering van embryotoxiciteit werd geevalueerd met carbamazepine als modelstof. Blootstelling via het kweekmedium leidde tot neuraalbuisdefecten, en blootstelling via amnionholte of exocoeloom veroorzaakte slechts lokale effecten. In overeenstemming hiermee was carbamazepine alleen detecteerbaar in embryonaal weefsel na blootstelling via het kweekmedium. Derhalve is de dosering via het kweekmedium de relevante blootstelling voor interne dosismodellering voor embryotoxische effecten en extrapolatie daarvan voor humane risicoevaluatie.The usefulness of postimplantation embryo culture for internal dose modelling in embryotoxicity testing was investigated using carbamazepine as a model compound. Exposure via the culture medium resulted in neural tube defects, whereas exposure via the amniotic or exocoelomic spaces caused local effects only. In accordance with these findings, only after culture medium exposure were amounts of carbamazepine detectable in the embryonic tissues. It is concluded that the dose taken up from the culture medium is the relevant dose to be used for internal dose modelling for embryotoxic effects and their extrapolation for human risk assessment.RIV

Toxicokinetiek van oraal toegediend lindaan (y-HCH) en diverse PCB-congeneren in de geit

In 1995 Olling et al. proposed a method to assess the body burden and daily absorption of a lipophilic contaminant in cattle both prospectively and retrospectively on the basis of only a limited number of measurements in milk, blood or fat. In order to validate the applicability of this method, it was decided to assess its performance by means of an experiment in goats who would receive known amounts of PCB congeners or lindane (y-HCH). Subsequently, contaminant concentrations in plasma and milkfat were measured. These results were incorporated into a PBPK model of the goat in order to describe the kinetics of the individual PCB congeners and lindane. Estimation of kinetic parameters was carried out by fitting them to the data in an automated procedure. The estimated standard physiological parameters of the goat together with the fitted kinetic parameter values have been implemented into an estimation module based on the assessment method. Part of the data has been used to estimate the known body burden and daily absorption. It appears that the method offers a good screening tool for gaining insight into current body burden and recent history of contamination of cattle.In 1995 is door Olling et al. een methode geintroduceerd om in landbouwhuisdieren te schatten wat de huidige lichaamsbelasting en de dagelijkse opname van een milieucontaminant in het recente verleden is geweest. Deze methode is gebaseerd op slechts enkele metingen in melk, bloed of vet. Het doel van de in dit rapport beschreven studie is deze methode van monstername te valideren en vervolgens hieruit een rekenmodule plus een Graphical User Interface (GUI) te ontwikkelen (zie ook RIVM-rapportnummer 643810005). Ter validatie van de methode is een experiment opgezet waarbij aan geiten hetzij PCBs, hetzij lindaan (y-HCH) is toegediend. Om de kinetiek van de afzondelijke PCBs en lindaan te beschrijven is een PBPK model voor de geit opgesteld. De geschatte standaard fysiologische parameters en de gevonden parameters zijn geomplementeerd in een schattingsmodule. Een deel van de data is vervolgens gebruikt om huidige lichaamsbelasting en dagelijkse absorptie in de geit te schatten. Het blijkt dat de methode goed gebruikt zou kunnen worden als een eerste test om inzicht te krijgen in de contaminatie van een bedrijf

Carry-over of dioxins and PCBs from feed and soil to eggs at low contamination levels : influence of binders on the carry-over from feed to eggs

In order to study the relationship between dioxin and PCB levels in feed and eggs, laying hens were fed with compound feed containing six different levels of dioxins, dioxin-like PCBs and indicator PCBs for a period of 56 days. This was followed by a period of another 56 days on clean feed.Data were successfully modelled in order to predict the levels after different exposure scenario’s. Overall, these data show that exposure to dioxins and dioxin-like PCBs rapidly results in increased levels in eggs and that the current EU limit for feed cannot guarantee egg levels below the EU-limit. Therefore, dioxin levels in chicken feed should be as low as possible and the current limit for dioxins in feed should be further reduced, at least in the case of chicken feeds. More in general, it is important to further harmonize the tolerance limits for feed and edible products like meat, eggs and milk. Information about the carry-over of contaminants in farm animals is essential for this purpose

The valatilization of some Chlorinated C-1, C-2 Alkanes, -Alkenes, and Dichlorobenzene from unsaturnated soils

Het rapport beschrijft de resultaten van een laboratoriumonderzoek naar de vervluchtiging van een aantal gechloreerde koolwaterstoffen die op grote schaal als industriele oplosmiddelen worden gebruikt en die frequent in grondwater worden aangetroffen. De resultaten van het experimentele onderzoek worden vergeleken met de uitkomsten van simulaties met een mathematisch model. Eveneens wordt onderzocht in hoeverre de vervluchtiging beinvloed wordt door de variatie in de veldomstandigheden. De resultaten tonen aan dat de laboratoriumopstelling geschikt is voor het traceren van de vervluchtiging in zeer lage concentraties en dat het mathematisch model deze vervluchtiging redelijk voorspelt. Het voorkomen van de verbindingen in grondwater lijkt verklaard te kunnen worden uit de variatie in temperatuur en verzadigingsgraad die t.g.v. neerslag en seizoenswisseling optreedt.DGMH/BWS-B /Willems