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Contains fulltext : 208573.pdf (publisher's version ) (Open Access), BACKGROUND: Poly (ADP-ribose) Polymerase (PARP) inhibitors are promising novel radiosensitisers. Pre-clinical models have demonstrated potent and tumour-specific radiosensitisation by PARP inhibitors. Olaparib is a PARP inhibitor with a favourable safety profile in comparison to clinically used radiosensitisers including cisplatin when used as single agent. However, data on safety, tolerability and efficacy of olaparib in combination with radiotherapy are limited. METHODS: Olaparib is dose escalated in combination with radical (chemo-)radiotherapy regimens for non-small cell lung cancer (NSCLC), breast cancer and head and neck squamous cell carcinoma (HNSCC) in three parallel single institution phase 1 trials. All trials investigate a combination treatment of olaparib and radiotherapy, the NSCLC trial also investigates a triple combination of olaparib, radiotherapy and concurrent low dose cisplatin. The primary objective is to identify the maximum tolerated dose of olaparib in these combination treatments, defined as the dose closest to but not exceeding a 15% probability of dose limiting toxicity. Each trial has a separate dose limiting toxicity definition, taking into account incidence, duration and severity of expected toxicities without olaparib. Dose escalation is performed using a time-to-event continual reassessment method (TITE-CRM). TITE-CRM enables the incorporation of late onset toxicity until one year after treatment in the dose limiting toxicity definition while maintaining an acceptable trial duration. Olaparib treatment starts two days before radiotherapy and continues during weekends until two days after radiotherapy. Olaparib will also be given two weeks and one week before radiotherapy in the breast cancer trial and HNSCC trial respectively to allow for translational research. Toxicity is scored using common terminology criteria for adverse events (CTCAE) version 4.03. Blood samples, and tumour biopsies in the breast cancer trial, are collected for

Item does not contain fulltext, BACKGROUND: Stroke is an important cause of death and disability worldwide. Since high blood pressure is an important risk factor for stroke and stroke recurrence, drugs that lower blood pressure might play an important role in secondary stroke prevention. OBJECTIVES: To investigate whether blood pressure-lowering drugs (BPLDs) started at least 48 hours after the index event are effective for the prevention of recurrent stroke, major vascular events, and dementia in people with stroke or transient ischaemic attack (TIA). Secondary objectives were to identify subgroups of people in which BPLDs are effective, and to investigate the optimum systolic blood pressure target after stroke or TIA for preventing recurrent stroke, major vascular events, and dementia. SEARCH METHODS: In August 2017, we searched the Trials Registers of the Cochrane Stroke Group and the Cochrane Hypertension Group, the Cochrane Central Register of Controlled Trials (CENTRAL; 2017, Issue 8), MEDLINE Ovid (1946 to August 2017), Embase Ovid (1974 to August 2017), ClinicalTrials.gov, the ISRCTN Registry, Stroke Trials Registry, Trials Central, and the World Health Organization (WHO) International Clinical Trials Registry Platform Portal. SELECTION CRITERIA: Randomised controlled trials (RCTs) of BPLDs started at least 48 hours after stroke or TIA. DATA COLLECTION AND ANALYSIS: Two review authors independently screened all titles and abstracts, selected eligible trials, extracted the data, assessed risk of bias, and used GRADE to assess the quality of the evidence. If necessary, we contacted the principal investigators or corresponding authors for additional data. MAIN RESULTS: We included 11 studies involving a total of 38,742 participants: eight studies compared BPLDs versus placebo or no treatment (35,110 participants), and three studies compared different systolic blood pressure targets (3632 participants). The risk of bias varied greatly between included studies. The pooled risk ratios (RRs) of B

Item does not contain fulltext, BACKGROUND: PARP inhibitors are currently evaluated in combination with radiotherapy and/or chemotherapy. As sensitizers, PARP inhibitors are active at very low concentrations therefore requiring highly sensitive pharmacodynamic (PD) assays. Current clinical PD-assays partly fail to provide such sensitivities. The aim of our study was to enable sensitive PD evaluation of PARP inhibitors for clinical sensitizer development. MATERIAL AND METHODS: PBMCs of healthy individuals and of olaparib and radiotherapy treated lung cancer patients were collected for ELISA-based PD-assays. RESULTS: PAR-signal amplification by ex vivo irradiation enabled an extended quantification range for PARP inhibitory activities after ex vivo treatment with inhibitors. This "radiation-enhanced-PAR" (REP) assay provided accurate IC50 values thereby also revealing differences among healthy individuals. Implemented in clinical radiotherapy combination Phase I trials, the REP-assay showed sensitive detection of PARP inhibition in patients treated with olaparib and establishes strong PARP inhibitory activities at low daily doses. CONCLUSIONS: Combination trials of radiotherapy and novel targeted agent(s) often require different and more sensitive PD assessments than in the monotherapy setting. This study shows the benefit and relevance of sensitive and adapted PD-assays for such combination purposes and provides proof of clinically relevant cellular PARP inhibitory activities at low daily olaparib doses.

Item does not contain fulltext, AIM: The current literature shows no consensus on the localization and number of characteristic neuronal inclusions [p62 and dipeptide repeat proteins (DRPs) positive, TDP-43-negative and TDP-43 positive] in the brain and spinal cord of patients with the hexanucleotide repeat expansion on chromosome 9 (C9ORF72-positive patients). This may be due to small sample sizes. A valid brain map of the inclusions in C9ORF72-positive patients may improve clinicopathological correlations and may serve as a reference for neuropathologists. METHODS: We performed a systematic review on 42 pathological studies to assess the pooled prevalence rates and density (a measure of the number of inclusions per brain region) of (phosphorylated)-TDP-43, p62 and DRP neuronal inclusions in seven brain regions and the spinal cord of 261 C9ORF72-positive patients with amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD) and ALS-FTD. RESULTS: In the cerebellum and hippocampus, the pooled prevalence rates of TDP-43 neuronal cytoplasmic inclusions (NCIs; cerebellum: 3.9%; hippocampus: 68.3%) were lower than those of DRP (cerebellum: 97.2%; hippocampus 97.1%). Moreover, TDP-43 inclusion density was lower compared with p62 inclusion density in these regions. The pooled prevalence rate of TDP-43 NCI in the substantia nigra was high (94.4%). DISCUSSION: The findings of this systematic review largely confirm findings of previous smaller studies on the localization and prevalence of inclusions in the central nervous system of C9ORF72-positive patients. The high prevalence of TDP-43 inclusions in the substantia nigra is a relatively new finding and is probably related to the relatively high prevalence of parkinsonism in C9ORF72-positive patients.

Item does not contain fulltext, BACKGROUND AND PURPOSE: The PARP inhibitor olaparib is currently tested in clinical phase 1 trials to define safe dose levels in combination with RT. However, certain clinically relevant insights are still lacking. Here we test, while comparing to single agent activity, the olaparib dose and genetic background dependence of olaparib-mediated radiosensitization. MATERIALS AND METHODS: Long-term growth inhibition and clonogenic assays were used to assess radiosensitization in BRCA2-deficient and BRCA2-complemented cells and in a panel of human head and neck squamous cell carcinoma cell lines. RESULTS: The extent of radiosensitization greatly depended on the olaparib dose, the radiation dose and the homologous recombination status of cells. Olaparib concentrations that resulted in radiosensitization prevented PAR induction by irradiation. Seven hours olaparib exposures were sufficient for radiosensitization. Importantly, the radiosensitizing effects can be observed at much lower olaparib doses than the single agent effects. CONCLUSION: Extrapolation of these data to the clinic suggests that low olaparib doses are sufficient to cause radiosensitization, underlining the potential of the treatment. Here we show that drug doses achieving radiosensitization can greatly differ from those achieving single agent activities, an important consideration when developing combined radiotherapy strategies with novel targeted agents.

Item does not contain fulltext, Cognitive change is frequently observed in patients with Parkinson's disease (PD). However, the exact profile and extent of cognitive impairments remain unclear due to the clinical heterogeneity of PD and methodological issues in many previous studies. In this study, we aimed to examine the severity, frequency, and profile of cognitive changes in newly diagnosed PD patients over 5 years. At baseline and after 3 and 5 years, a hospital-based sample of PD patients (n = 59) and healthy controls (n = 40) were given neuropsychological tests covering six cognitive domains. Patients showed greater decline over time than healthy controls on all cognitive domains, except for attention. The profile of decline showed that psychomotor speed and memory were most affected. At the individual level 53% of the patients showed more cognitive decline than controls. Age at onset and memory impairment at baseline predicted cognitive decline. Cognitive functions in PD patients show greater decline in most domains than in healthy elderly over the course of 5 years. Due to selection bias as a result of attrition, the actual degree of decline may be greater than reported here.

In de (glas)tuinbouw is hygiëne erg belangrijk om het gewas gezond en productief te houden. Vooral in het geval van circulatie van gewas en/of water is het noodzakelijk besmettingen tijdig te signaleren en maatregelingen te treffen om uitbreiding te voorkomen. Er bestaan verschillende toetsen en analyses om de verschillende hygiënesystemen op een tuinbouwbedrijf te controleren op afdoende werking.

Op basis van de tot nu toe opgedane praktijkervaringen kan worden geconcludeerd dat preventieve analyses met behulp van DNA multiscan zeer waardevolle informatie kan geven voor de tuinder. Hij weet met welke ziekten hij te maken heeft en kan effect van ziektebestrijding volgen in het recirculatiewater