Kankerrisico’s : kunnen we nog iets leren van de muis?

Niet UB, maar tijdelijk ter bevordering van de PDF bestanden in het Leids Repositorium

Toepassingsmogelijkheden van Modified Atmosphere Packaging (MAP) in rozen en sierheesters

Boomkwekerijgewassen, zoals rozen en siergewassen, zijn in diverse stadia van de keten gevoelig voor kwaliteitsverlies. Dit kan uitdroging zijn door vochttekort, verrotting bij vochtovermaat of ongewenst uitlopen van het product. Uit eerder onderzoek is gebleken dat toepassing van zogenaamde Modified Atmosphere folies (MA, zie kader) al dan niet in combinatie met bepaalde vulmiddelen dergelijke problemen sterk kan verminderen en daarmee de houdbaarheid van producten kan verlengen. Dit rapport geeft de resultaten van een onderzoek naar de mogelijkheden van toepassing van MA-folie bij bewaring van rozen en siergewassen in verschillende delen van de keten

Mammary gland tumor promotion by chronic administration of IGF1 and the insulin analogue AspB10 in the p53R270H/⁺WAPCre mouse model

Insulin analogues are structurally modified molecules with altered pharmaco-kinetic and -dynamic properties compared to regular human insulin used by diabetic patients. While these compounds are tested for undesired mitogenic effects, an epidemiological discussion is ongoing regarding an association between insulin analogue therapy and increased cancer incidence, including breast cancer. Standard in vivo rodent carcinogenesis assays do not pick up this possible increased carcinogenic potential. Here we studied the role of insulin analogues in breast cancer development. For this we used the human relevant mammary gland specific p53R270H/⁺WAPCre mouse model. Animals received life long repeated treatment with four different insulin (-like) molecules: normal insulin, insulin glargine, insulin X10 (AspB10) or insulin-like growth factor 1 (IGF1). Insulin-like molecules with strong mitogenic signaling, insulin X10 and IGF1, significantly decreased the time for tumor development. Yet, insulin glargine and normal insulin, did not significantly decrease the latency time for (mammary gland) tumor development. The majority of tumors had an epithelial to mesenchymal transition phenotype (EMT), irrespective of treatment condition. Enhanced extracellular signaling related kinase (Erk) or serine/threonine kinase (Akt) mitogenic signaling was in particular present in tumors from the insulin X10 and IGF1 treatment groups. These data indicate that insulin-like molecules with enhanced mitogenic signaling increase the risk of breast cancer development. Moreover, the use of a tissue specific cancer model, like the p53R270H/⁺WAPCre mouse model, is relevant to assess the intrinsic pro-carcinogenic potential of mitogenic and non-mitogenic biologicals such as insulin analogues. INTRODUCTION METHODS RESULTS CONCLUSION

Onderzoek naar het bemestingsadvies van vruchtbomen, coniferen, rozen en buxus

In 2006 is het stelsel van gebruiksnormen ingevoerd. Deze normen zijn gebaseerd op de bestaande bemestingsadviezen. Kwekers van vruchtbomen, coniferen, rozen en Buxus hebben aangegeven dat de stikstofgebruiksnormen te laag zijn om een rendabele kwaliteitsproductie te behalen. Dit betekent dat de adviezen aangepast moeten worden. Een belangrijke reden om een aanpassing van het advies en daarmee de gebruiksnorm te vragen is dat er in de periode tussen het verschijnen van de Bemestingsadviesbasis boomkwekerijgewassen en het vaststellen van de stikstofgebruiksnormen er veel zaken in de teelt van de desbetreffende gewassen is veranderd. Daarnaast zijn de bestaande adviezen veelal gebaseerd op ‘expert knowledge’ en slechts beperkt op veldproeven. Om tot een aanpassing van het bemestingsadvies te komen moeten bemestingsproeven worden uitgevoerd volgens het ‘Protocol voor de aanpassing bemestingsadviezen voor stikstof’. In dit rapport worden de proeven beschreven die voor de vier genoemde gewasgroepen gedurende een aantal jaren zijn uitgevoer

TP53 and lacZ mutagenesis induced by 3-nitrobenzanthrone in Xpa-deficient human TP53 knock-in mouse embryo fibroblasts

Abstract3-Nitrobenzanthrone (3-NBA) is a highly mutagenic compound and possible human carcinogen found in diesel exhaust. 3-NBA forms bulky DNA adducts following metabolic activation and induces predominantly G:C>T:A transversions in a variety of experimental systems. Here we investigated the influence of nucleotide excision repair (NER) on 3-NBA-induced mutagenesis of the human tumour suppressor gene TP53 and the reporter gene lacZ. To this end we utilised Xpa -knockout (Xpa-Null) human TP53 knock-in (Hupki) embryo fibroblasts (HUFs). As Xpa is essential for NER of bulky DNA adducts, we hypothesized that DNA adducts induced by 3-NBA would persist in the genomes of Xpa-Null cells and lead to an increased frequency of mutation. The HUF immortalisation assay was used to select for cells harbouring TP53 mutations following mutagen exposure. We found that Xpa-Null Hupki mice and HUFs were more sensitive to 3-NBA treatment than their wild-type (Xpa-WT) counterparts. However, following 3-NBA treatment and immortalisation, a similar frequency of TP53-mutant clones arose from Xpa-WT and Xpa-Null HUF cultures. In cells from both Xpa genotypes G:C>T:A transversion was the predominant TP53 mutation type and mutations exhibited bias towards the non-transcribed strand. Thirty-two percent of 3-NBA-induced TP53 mutations occurred at CpG sites, all of which are hotspots for mutation in smokers’ lung cancer (codons 157, 158, 175, 245, 248, 273, 282). We also examined 3-NBA-induced mutagenesis of an integrated lacZ reporter gene in HUFs, where we again observed a similar mutant frequency in Xpa-WT and Xpa-Null cells. Our findings suggest that 3-NBA-DNA adducts may evade removal by global genomic NER; the persistence of 3-NBA adducts in DNA may be an important factor in its mutagenicity

Biomarkers for circadian rhythm disruption independent of time of day

Frequent shift work causes disruption of the circadian rhythm and might on the long-term result in increased health risk. Current biomarkers evaluating the presence of circadian rhythm disturbance (CRD), including melatonin, cortisol and body temperature, require 24-hr ("around the clock") measurements, which is tedious. Therefore, these markers are not eligible to be used in large-scale (human) studies.

Clinical decision rules and measuring renal function in community pharmacy: what do we get out of it?

OBJECTIVE To investigate the frequency and management of drug therapy alerts about drug use in patients with (potential) renal impairment, to investigate the contribution of point-of-care testing (PoCT) of renal function in community pharmacy to the availability of information on renal function, and to investigate pharmacists’ experiences with drug therapy alerts and PoCT. DESIGN AND METHODS A clinical decision support system with clinical decision rules for eleven drugs (seven antibiotics, sotalol, digoxin, allopurinol and spironolactone) and PoCT of renal function were implemented in community pharmacies. The clinical decision rules generated an alert when dose adjustment was advised based on a registered impaired renal function, and when information on the renal function was lacking for patients over 70 years of age with a prescription for one of the selected drugs. Data registered in the clinical decision support system regarding generated alerts, renal functions and alert management were analysed retrospectively. In addition, the participating pharmacists filled out a questionnaire about their experiences. RESULTS 336 pharmacists managed 27.307 alerts for 21.494 patients, leading to 362 dose adjustments and 65 drug replacements. For 16.208 of these patients, renal function has been registered in the clinical decision support system, including over 400 PoCT measurements. Based on PoCT, 25 cases of impaired renal function have been registered, leading to two therapy adjustments. The participating pharmacists were positive about the project. CONCLUSION Advanced clinical decision rules on renal function led to over 400 therapy adjustments. PoCT is a potentially useful source of information on renal function in a limited number of cases, when this information is urgently needed and not available from other sources

The transcriptomic response to irinotecan in colon carcinoma bearing mice preconditioned by fasting

Background: Irinotecan use is limited due to severe toxicity. Preconditioning by fasting (PBF) protects against side effects of irinotecan while preserving its antitumor activity. The mechanisms underlying the effects of PBF still need to be elucidated. Here, we investigated the transcriptional responses of PBF on irinotecan in both tumor and healthy liver tissue. Experimental approach: Male BALB/c mice were subcutaneously injected with C26 colon carcinoma cells. Twelve days after tumor inoculation, two groups were fasted for three days and two groups were allowed food ad libitum (AL). Subsequently, both groups received one dose of irinotecan. Twelve hours after administration mice were sacrificed and blood, tumor and liver tissue were harvested. Blood samples were analyzed to determine liver, kidney and bone marrow function, tissues were used for transcriptome analyses. Key results: The AL irinotecan group showed worsened organ function and decreased leukocyte numbers. These effects were abated in PBF animals. PBF led to an altered transcriptional response in the liver of irinotecan-treated mice, including decreased cellular injury and increased stress resistance. Hepatic metabolism of irinotecan was also significantly changed due to PBF. The transcriptional response of tumor tissue observed after PBF was hardly affected compared to AL fed animals. Conclusions: Transcriptional changes after PBF to irinotecan treatment showed an improved protective stress response in healthy liver but not in tumor tissue, including changes in irinotecan metabolism. These data help to unravel the mechanisms underlying the effects of fasting on irinotecan and help to improve outcome of chemotherapeutic treatment in cancer patients

The role of rectal chloride secretion in childhood constipation

Background Disturbance in fluid secretion, driven by chloride secretion, might play a role in constipation. However, disturbed chloride secretion in those patients has yet to be evaluated. Therefore, the aim of this study was to compare chloride secretion in rectal biopsies of children with functional constipation (FC) to those without constipation. Methods To measure changes in short circuit current (Iscin μAcm-2) reflecting chloride secretion, intestinal biopsies from chi