Epidrug-induced upregulation of functional somatostatin type 2 receptors in human pancreatic neuroendocrine tumor cells

Somatostatin receptors are a pivotal target for treatment of pancreatic neuroendocrine tumors (pNET), either with somatostatin analogues (SSA) or radiolabeled SSA. The highest affinity target for the most commonly used SSA is the somatostatin receptor type 2 (sst2). An important factor that may complicate treatment efficacy, is the variable number of receptors expressed on pNETs. Gene expression is subject to complex regulation, in which epigenetics has a central role. In this study we explored the possible role of epigenetic modifications in the variations in sst2 expression levels in two human pNET cell lines, BON-1 and QGP-1. We found upregulation of sst2 mRNA after treatment with the epidrugs 5-aza-2'-deoxycytidine (5-aza-dC) and valproic acid (VPA), an increased uptake of radiolabeled octreotide, as well as increased sensitivity to the SSA octreotide in functional cAMP inhibition. At epigenetic level we observed low methylation levels of the sst2 gene promoter region irrespective of expression. Activating histone mark H3K9Ac can be regulated with epidrug treatment, with an angle of effect corresponding to the effect on mRNA expression. Repressive histone mark H3K27me3 is not regulated by either 5-aza-dC or VPA. We conclude that epidrug treatment, in particular with combined 5-aza-dC and VPA treatment, might hold promise for improving and adding to current SSA treatment strategies of patients with pNETs

ADAM12 is a circulating marker for stromal activation in pancreatic cancer and predicts response to chemotherapy

Pancreatic ductal adenocarcinoma (PDAC) is characterized by abundant stroma that harbors tumor-promoting properties. No good biomarkers exist to monitor the effect of stromal targeting therapies or to predict response. We set out to identify such non-invasive markers for PDAC stroma and predict response to therapy. Gene expression datasets, co-culture experiments, xenografts, and patient samples were analyzed. Serum samples were measured from a cohort of 58 resected patients, and 87 metastatic or locally advanced PDAC patients. Baseline and follow-up levels were assessed in 372 additional metastatic PDAC patients who received nab-paclitaxel with gemcitabine (n = 184) or gemcitabine monotherapy (n = 188) in the phase III MPACT trial. Increased levels of ADAM12 were found in PDAC patients compared to healthy controls (p < 0.0001, n = 157 and n = 38). High levels of ADAM12 significantly associated with poor outcome in resected PDAC (HR 2.07, p = 0.04). In the MPACT trial survival was significantly longer for patients who received nab-paclitaxel and had undetectable ADAM12 levels before treatment (OS 12.3 m vs 7.9 m p = 0.0046). Consistently undetectable or decreased ADAM12 levels during treatment significantly associated with longer survival as well (OS 14.4 m and 11.2 m, respectively vs 8.3, p = 0.0054). We conclude that ADAM12 is a blood-borne proxy for stromal activation, the levels of which have prognostic significance and correlate with treatment benefit

Search for Neutrinoless Double- β Decay with the Complete EXO-200 Dataset

A search for neutrinoless double-β decay (0νββ) in Xe136 is performed with the full EXO-200 dataset using a deep neural network to discriminate between 0νββ and background events. Relative to previous analyses, the signal detection efficiency has been raised from 80.8% to 96.4±3.0%, and the energy resolution of the detector at the Q value of Xe136 0νββ has been improved from σ/E=1.23% to 1.15±0.02% with the upgraded detector. Accounting for the new data, the median 90% confidence level 0νββ half-life sensitivity for this analysis is 5.0×1025 yr with a total Xe136 exposure of 234.1 kg yr. No statistically significant evidence for 0νββ is observed, leading to a lower limit on the 0νββ half-life of 3.5×1025 yr at the 90% confidence level

Anticoagulation with or without Clopidogrel after Transcatheter Aortic-Valve Implantation

BACKGROUND The roles of anticoagulation alone or with an antiplatelet agent after transcatheter aortic-valve implantation (TAVI) have not been well studied. METHODS We performed a randomized trial of clopidogrel in patients undergoing TAVI who were receiving oral anticoagulation for appropriat

Non-AIDS defining cancers in the D:A:D Study-time trends and predictors of survival : a cohort study

BACKGROUND:Non-AIDS defining cancers (NADC) are an important cause of morbidity and mortality in HIV-positive individuals. Using data from a large international cohort of HIV-positive individuals, we described the incidence of NADC from 2004-2010, and described subsequent mortality and predictors of these.METHODS:Individuals were followed from 1st January 2004/enrolment in study, until the earliest of a new NADC, 1st February 2010, death or six months after the patient's last visit. Incidence rates were estimated for each year of follow-up, overall and stratified by gender, age and mode of HIV acquisition. Cumulative risk of mortality following NADC diagnosis was summarised using Kaplan-Meier methods, with follow-up for these analyses from the date of NADC diagnosis until the patient's death, 1st February 2010 or 6 months after the patient's last visit. Factors associated with mortality following NADC diagnosis were identified using multivariable Cox proportional hazards regression.RESULTS:Over 176,775 person-years (PY), 880 (2.1%) patients developed a new NADC (incidence: 4.98/1000PY [95% confidence interval 4.65, 5.31]). Over a third of these patients (327, 37.2%) had died by 1st February 2010. Time trends for lung cancer, anal cancer and Hodgkin's lymphoma were broadly consistent. Kaplan-Meier cumulative mortality estimates at 1, 3 and 5 years after NADC diagnosis were 28.2% [95% CI 25.1-31.2], 42.0% [38.2-45.8] and 47.3% [42.4-52.2], respectively. Significant predictors of poorer survival after diagnosis of NADC were lung cancer (compared to other cancer types), male gender, non-white ethnicity, and smoking status. Later year of diagnosis and higher CD4 count at NADC diagnosis were associated with improved survival. The incidence of NADC remained stable over the period 2004-2010 in this large observational cohort.CONCLUSIONS:The prognosis after diagnosis of NADC, in particular lung cancer and disseminated cancer, is poor but has improved somewhat over time. Modifiable risk factors, such as smoking and low CD4 counts, were associated with mortality following a diagnosis of NADC

Realised capacity estimation with use of vertical queuing method: Improving the method of estimating the overall effect of traffic measures on the vehicle delay time at the Dutch national freeway network

The topic at which this thesis is based on is the effect of traffic measures at the vehicle delay time, VDT. The research focused towards the capacity effect of traffic measures. The effectiveness of traffic management measures is determined by their effect on the VDT. However, the development of the VDT is not singular influenced by the installation of measures. The challenge within the main topic is to unravel the total change of VDT into the contributions of all influencing factors. Within this thesis, the vertical queuing model is used to estimate the realised capacity, i.e. the actual achieved throughput during a congestion period under the prevailing conditions. Regression analysis estimates the contribution of the different individual influencing factors, such as traffic management measures, on the realised capacity. The vertical queuing model uses the principle of first-in-first-out. Road sections are individually examined. The model is based on the count of the number of arriving and departing vehicles during the day. It is assumed that the total daily demand is served, i.e. eventually all traffic will pass the road section. All vehicles can pass without any delay as long as the demand does not exceed the capacity. A queue will build up in the model as soon as the demand does exceed the capacity. The arrivals are determined by the demand and can be deduced from the traffic flow. The departures are restricted by the number of arrivals or by the capacity. While the VDT is measured, the queue length and therefore the difference between the cumulative arrivals and departures can be calculated. The total number of departures and arrivals before the beginning of a congestion period as well as directly after the congestion period are based on the measured traffic flows. The estimated realised capacity is the average traffic flow during the congestion period. The estimated realised capacity should be explained by the prevailing conditions. Regression analysis based on many records can estimate the effects of all the influencing factors. So in essence, the capacity is the variable in the model that is estimated based on the measured VDT and the measured cumulative traffic volumes. The regression analysis estimates effects and these effects can be transferred to effects on the VDT. The main conclusion is that it is possible to implement the vertical queuing model and to estimate effects of influencing factors on the capacity. The calculation of the effect on VDT is also possible, only there is need for further research to improve the estimation of the effect of prevented congestion periods. There now is a direct relation between measured traffic data and the effect of traffic management measures. It is also possible to unravel the effects of other factors such as adverse weather conditions.Transport & PlanningCivil Engineering and Geoscience

Transcriptomics and Proteomics Methods for Xenopus Embryos and Tissues

Contains fulltext : 214241.pdf (publisher's version ) (Open Access

Genomics Methods for Xenopus Embryos and Tissues

Contains fulltext : 226859.pdf (publisher's version ) (Closed access

Clustering semantics for hypermedia presentation

Semantic annotations of media repositories make relationships among the stored media and relevant concepts explicit. However, these relationships and the media they join are not directly presentable as hypermedia. Previous work shows how clustering over the annotations in the repositories can determine hypermedia presentation structure. Here we explore the application of different clustering techniques to generating hypermedia interfaces to media archives. This paper also describes the effect of each type of clustering on the end user's experience. We then generalize and unify these techniques with the use of proximity measures in further improving generated presentation structur