The apoptotic and proliferation rate of tumour budding cells in colorectal cancer outlines a heterogeneous population of cells with various impacts on clinical outcome

AIMS In colorectal cancer (CRC), tumour buds represent an aggressive cell type at the invasive front with apparently low proliferation. The aim of this study was to determine proliferation and apoptotic rates of buds in comparison to tumour centre, front and mucosa. METHODS AND RESULTS Whole tissue sections from 188 CRC patients underwent immunohistochemistry for Ki67. Ten high-power fields (HPFs) were evaluated in mucosa, tumour centre, tumour front and tumour buds (total = 40 HPFs/case). Caspase-3 and M30 immunohistochemistry were performed on a multipunch tissue microarray from the same cohort. Ki67, caspase-3 and M30 immunoreactivity were correlated with outcome. The average percentage of cells showing Ki67 positivity was 5.2% in mucosa, and was not significantly different between the centre and front of the tumour (38.2% and 34.9%; P < 0.0001); 0.3% of buds showed Ki67 positivity (P < 0.0001). Caspase-3 expression was similar in mucosa, tumour centre and tumour front, but lower in tumour buds (<0.1%; P < 0.0001). M30 staining in buds was decreased (0.01%; P < 0.0001) in comparison to other areas. Ki67 positivity in buds was detrimental to survival in univariate (P = 0.0352) and multivariate (P = 0.0355) analysis. Caspase-3-positive tumours showed better outcome than negative tumours (P = 0.0262); but tumours with caspase-3-positive buds showed a worse outcome than those with caspase-3-negative buds (P = 0.0235). CONCLUSIONS Ki67, caspase-3 and M30 staining is absent in most tumour buds, suggesting decreased proliferation and apoptosis. However, the fact that Ki67 and caspase-3 immunoreactivity was associated with unfavourable prognosis points to a heterogeneous population of tumour buds.

A comparison between the chemical behaviour of lead-gold and lead-bismuth eutectics towards 316L stainless steel

Lead-gold eutectic (LGE) has been recently proposed as an alternative target material for high power spallation sources. In order to compare the corrosive properties of LGE to the better-studied eutectic of lead-bismuth (LBE), an isothermal twin-loop made of SS 316L was built and operated at the Institute of Physics of the University of Latvia. We have measured the concentration of steel alloying elements dissolved in both alloys at the end of two test campaigns via ICP-OES. In case of LGE, a pronounced concentration increase of Fe, Ni, Mn and Cr is found in the liquid metal, which is significantly higher compared to LBE. Similar results were obtained during complementary investigations on material samples exposed to both alloys in this twin-loop at 400 ◦C and 450 ◦C. These findings indicate that in contact with LGE, SS 316L steel suffers from substantial chemical attack. Detailed investigations using structure materials other than SS 316L have to be undertaken before qualifying LGE as a serious alternative to LBE.

5-year results comparing mineral trioxide aggregate and adhesive resin composite for root-end sealing in apical surgery

INTRODUCTION Recent meta-analyses of the outcome of apical surgery using modern techniques including microsurgical principles and high-power magnification have yielded higher rates of healing. However, the information is mainly based on 1- to 2-year follow-up data. The present prospective study was designed to re-examine a large sample of teeth treated with apical surgery after 5 years. METHODS Patients were recalled 5 years after apical surgery, and treated teeth were classified as healed or not healed based on clinical and radiographic examination. (The latter was performed independently by 3 observers). Two different methods of root-end preparation and filling (primary study parameters) were to be compared (mineral trioxide aggregate [MTA] vs adhesive resin composite [COMP]) without randomization. RESULTS A total of 271 patients and teeth from a 1-year follow-up sample of 339 could be re-examined after 5 years (dropout rate = 20.1%). The overall rate of healed cases was 84.5% with a significant difference (P = .0003) when comparing MTA (92.5%) and COMP (76.6%). The evaluation of secondary study parameters yielded no significant difference for healing outcome when comparing subcategories (ie, sex, age, type of tooth treated, post/screw, type of surgery). CONCLUSIONS The results from this prospective nonrandomized clinical study with a 5-year follow-up of 271 teeth indicate that MTA exhibited a higher healing rate than COMP in the longitudinal prognosis of root-end sealing.

Increased number of non-degranulated mast cells in pancreatic ductal adenocarcinoma but not in acute pancreatitis.

Increasing evidence indicates that tumor microenvironment (TME) is crucial in tumor survival and metastases. Inflammatory cells accumulate around tumors and strangely appear to be permissive to their growth. One key stroma cell is the mast cell (MC), which can secrete numerous pro- and antitumor molecules. We investigated the presence and degranulation state of MC in pancreatic ductal adenocarcinoma (PDAC) as compared to acute ancreatitis (AP). Three different detection methods: (a) toluidine blue staining, as well as immunohistochemistry for (b) tryptase and (c) c-kit, were utilized to assess the number and extent of degranulation of MC in PDAC tissue (n=7), uninvolved pancreatic tissue derived from tumor-free margins (n=7) and tissue form AP (n=4). The number of MC detected with all three methods was significantly increased in PDAC, as compared to normal pancreatic tissue derived from tumor-free margins (p<0.05). The highest number of MC was identified by c-kit, 22.2∓7.5 per high power field (HPF) in PDAC vs 9.7∓5.1 per HPF in normal tissue. Contrary to MC in AP, where most of the detected MC were found degranulated, MC in PDAC appeared intact. In conclusion, MC are increased in number, but not degranulated in PDAC, suggesting that they may contribute to cancer growth by permitting selective release of pro-tumorogenic molecules.

Prioritizing – the task strategy of the powerful?

Previous research has shown that power increases focus on the main goal when distractor information is present. As a result, high-power people have been described as goal-focused. In real life, one typically wants to pursue multiple goals at the same time. There is a lack of research on how power affects how people deal with situations in which multiple important goals are present. To address this question, 158 participants were primed with high or low power or assigned to a control condition, and were asked to perform a dual-goal task with three difficulty levels. We hypothesized and found that high-power primed people prioritize when confronted with a multiple-goal situation. More specifically, when task demands were relatively low, power had no effect; participants generally pursued multiple goals in parallel. However, when task demands were high, the participants in the high-power condition focused on a single goal whereas participants in the low-power condition continued using a dual-task strategy. This study extends existing power theories and research in the domain of goal pursuit.

Tumor budding in colorectal cancer revisited: results of a multicenter interobserver study.

Tumor budding in colorectal cancer (CRC) is recognized as a valuable prognostic factor but its translation into daily histopathology practice has been delayed by lack of agreement on the optimal method of assessment. Within the context of the Swiss Association of Gastrointestinal Pathology (SAGIP), we performed a multicenter interobserver study on tumor budding, comparing hematoxylin and eosin (H&E) with pan-cytokeratin staining using a 10 high power field (10HPF) and hotspot (1HPF) method. Two serial sections of 50 TNM stage II-IV surgically treated CRC were stained for H&E and pan-cytokeratin. Tumor buds were scored by independent observers at six participating centers in Switzerland and Austria using the 10HPF and 1HPF method on a digital pathology platform. Pearson correlation (r) and intra-class correlation coefficients (ICC) comparing scores between centers were calculated. Three to four times more tumor buds were detected in pan-cytokeratin compared to H&E slides. Correlation coefficients for tumor budding counts between centers ranged from r = 0.46 to r = 0.91 for H&E and from r = 0.73 to r = 0.95 for pan-cytokeratin slides. Interobserver agreement across all centers was excellent for pan-cytokeratin [10HPF: ICC = 0.83 and 1HPF: ICC = 0.8]. In contrast, assessment of tumor budding on H&E slides reached only moderate agreement [10HPF: ICC = 0.58 and 1HPF: ICC = 0.49]. Based on previous literature and our findings, we recommend (1) pan-cytokeratin staining whenever possible, (2) 10HPF method for resection specimens, and (3) 1HPF method for limited material (preoperative biopsy or pT1). Since tumor budding counts can be used to determine probabilities of relevant outcomes and as such more optimally complement clinical decision making, we advocate the avoidance of cutoff scores.

Symptoms Have Modest Accuracy in Detecting Endoscopic and Histologic Remission in Adults With Eosinophilic Esophagitis.

BACKGROUND & AIMS It is not clear whether symptoms alone can be used to estimate the biologic activity of eosinophilic esophagitis (EoE). We aimed to evaluate whether symptoms can be used to identify patients with endoscopic and histologic features of remission. METHODS Between April 2011 and June 2014, we performed a prospective, observational study and recruited 269 consecutive adults with EoE (67% male; median age, 39 years old) in Switzerland and the United States. Patients first completed the validated symptom-based EoE activity index patient-reported outcome instrument and then underwent esophagogastroduodenoscopy with esophageal biopsy collection. Endoscopic and histologic findings were evaluated with a validated grading system and standardized instrument, respectively. Clinical remission was defined as symptom score <20 (range, 0-100); histologic remission was defined as a peak count of <20 eosinophils/mm(2) in a high-power field (corresponds to approximately <5 eosinophils/median high-power field); and endoscopic remission as absence of white exudates, moderate or severe rings, strictures, or combination of furrows and edema. We used receiver operating characteristic analysis to determine the best symptom score cutoff values for detection of remission. RESULTS Of the study subjects, 111 were in clinical remission (41.3%), 79 were in endoscopic remission (29.7%), and 75 were in histologic remission (27.9%). When the symptom score was used as a continuous variable, patients in endoscopic, histologic, and combined (endoscopic and histologic remission) remission were detected with area under the curve values of 0.67, 0.60, and 0.67, respectively. A symptom score of 20 identified patients in endoscopic remission with 65.1% accuracy and histologic remission with 62.1% accuracy; a symptom score of 15 identified patients with both types of remission with 67.7% accuracy. CONCLUSIONS In patients with EoE, endoscopic or histologic remission can be identified with only modest accuracy based on symptoms alone. At any given time, physicians cannot rely on lack of symptoms to make assumptions about lack of biologic disease activity in adults with EoE. ClinicalTrials.gov, Number: NCT00939263.

Radiochemical Determination of Rare Earth Elements in Proton-Irradiated Lead–Bismuth Eutectic

Various types of proton-irradiated lead–bismuth eutectic (LBE) samples from the MEGAPIE prototype spallation target were analyzed concerning their content of 148Gd, 173Lu, and 146Pm by use of α- and γ-spectrometry. A radiochemical separation procedure was developed to isolate the lanthanide fraction and to prepare thin samples for α-ray measurement. The results prove a substantial depletion of these three elements in bulk samples, whereas accumulation on the LBE/steel-interfaces was observed. The amount of material accumulated on surfaces was roughly estimated by relating the values measured on the sample surfaces to the total surface of the inner target walls. The amount of 148Gd, 173Lu, and 146Pm was then quantified by summing up the contributions from every sample type. The results show a reasonable agreement with theoretical predictions. The obtained results are of utmost importance for the evaluation of the performance of high-power spallation targets, especially concerning the residual nuclide production, the physicochemical behavior of the produced radionuclides during operation, and in terms of an intermediate or final disposal.

Nonlinear tests for genetic studies of complex disease

Linkage and association studies are major analytical tools to search for susceptibility genes for complex diseases. With the availability of large collection of single nucleotide polymorphisms (SNPs) and the rapid progresses for high throughput genotyping technologies, together with the ambitious goals of the International HapMap Project, genetic markers covering the whole genome will be available for genome-wide linkage and association studies. In order not to inflate the type I error rate in performing genome-wide linkage and association studies, multiple adjustment for the significant level for each independent linkage and/or association test is required, and this has led to the suggestion of genome-wide significant cut-off as low as 5 × 10 −7. Almost no linkage and/or association study can meet such a stringent threshold by the standard statistical methods. Developing new statistics with high power is urgently needed to tackle this problem. This dissertation proposes and explores a class of novel test statistics that can be used in both population-based and family-based genetic data by employing a completely new strategy, which uses nonlinear transformation of the sample means to construct test statistics for linkage and association studies. Extensive simulation studies are used to illustrate the properties of the nonlinear test statistics. Power calculations are performed using both analytical and empirical methods. Finally, real data sets are analyzed with the nonlinear test statistics. Results show that the nonlinear test statistics have correct type I error rates, and most of the studied nonlinear test statistics have higher power than the standard chi-square test. This dissertation introduces a new idea to design novel test statistics with high power and might open new ways to mapping susceptibility genes for complex diseases. ^

Detecting genetic and nutritional lung cancer risk factors related to folate metabolism using Bayesian generalized linear models

Complex diseases, such as cancer, are caused by various genetic and environmental factors, and their interactions. Joint analysis of these factors and their interactions would increase the power to detect risk factors but is statistically. Bayesian generalized linear models using student-t prior distributions on coefficients, is a novel method to simultaneously analyze genetic factors, environmental factors, and interactions. I performed simulation studies using three different disease models and demonstrated that the variable selection performance of Bayesian generalized linear models is comparable to that of Bayesian stochastic search variable selection, an improved method for variable selection when compared to standard methods. I further evaluated the variable selection performance of Bayesian generalized linear models using different numbers of candidate covariates and different sample sizes, and provided a guideline for required sample size to achieve a high power of variable selection using Bayesian generalize linear models, considering different scales of number of candidate covariates. ^ Polymorphisms in folate metabolism genes and nutritional factors have been previously associated with lung cancer risk. In this study, I simultaneously analyzed 115 tag SNPs in folate metabolism genes, 14 nutritional factors, and all possible genetic-nutritional interactions from 1239 lung cancer cases and 1692 controls using Bayesian generalized linear models stratified by never, former, and current smoking status. SNPs in MTRR were significantly associated with lung cancer risk across never, former, and current smokers. In never smokers, three SNPs in TYMS and three gene-nutrient interactions, including an interaction between SHMT1 and vitamin B12, an interaction between MTRR and total fat intake, and an interaction between MTR and alcohol use, were also identified as associated with lung cancer risk. These lung cancer risk factors are worthy of further investigation.^

Spectral reflectance of ODP Leg 178 holes

The routine use of spectrophotometry on the sediment surfaces of archive halves of each section during the onboard sedimentological core description process is a great stride toward development of real-time noninvasive characterization of deep-sea sediments. Spectral reflectance data have been used so far for mineral composition studies as well as for lithostratigraphic correlation between sites (Balsam and Deaton, 1991; Balsam et al., 1997; Mix et al., 1995; Ortiz et al., 1999). Their results demonstrate that spectrophotometry can estimate CaCO3 content by using the 4.65-, 5.25-, and 5.55-µm wavelength spectrums. A detailed overview of various other noninvasive methods is given in Ortiz and Rack (1999). The purpose of this study is to test whether spectrophotometry in the visible band can be used as a tool to gather further information about grain-size variation, sorting, compaction, and porosity, which are directly linked to the sedimentation process. From remote sensing data analyses, it is known that diffuse spectral reflectance data in the visible band in the wavelength window of 7.0-6.5 µm are sensitive to grain-size variations. It appears that a relationship between grain size and signal absorption exists only in this wavelength window. (e.g., Clark, 1999; Gaffey, 1986; Gaffey et al., 1993). Variations in grain size during a sedimentation process are linked to depositional energy, which affects sorting, compaction, and porosity of sediment deposits. As an example, we study here the spectrophotometric data of the sedimentary sequence of Hole 1098C, which was deposited under widely varying environmental conditions. Alternating turbidite and finely laminated sediments were recovered from Hole 1098C. The turbidites are related to a high depositional energy environment; the finely laminated sediments are related to a low depositional energy environment. Data from Hole 1098C were therefore used to test whether the spectral reflectance data can provide a proxy for these different depositional environments.

Geochemistry of bulk sediment from the Cape Basin

A technique for onsite application of X-ray fluorescence (XRF) spectrometry to samples from sediment cores aboard a research vessel was developed and tested. The method is sufficiently simple, precise, and fast to be used routinely for high-resolution analyses of depth profiles as well as surface samples. Analyses were performed with the compact high-performance energy-dispersive polarisation X-ray fluorescence (EDPXRF) analyser Spectro Xepos. Contents of the elements Si, Ti, Al, Fe, Mn, Mg, Ca, K, Sr, Ba, Rb, Cu, Ni, Zn, P, S, Cl and Br were simultaneously determined on 200-225 samples of each core within 24 h of recovery. This study presents a description of the employed shipboard preparation and analysis technique, along with some example data. We show land-based datasets that support our decisions to use powder samples and to reduce the original measuring time for onboard analyses. We demonstrate how well the results from shipboard measurements for the various elements compare with the land-based findings. The onboard geochemical data enabled us to establish an element stratigraphy already during the cruise. Correlation of iron, calcium and silicon enrichment trends with an older reference core provided an age model for the newly retrieved cores. The Spectro Xepos instrument performed without any analytical and technical difficulties which could have been caused by rougher weather conditions or continuous movement and vibration of the research vessel. By now, this XRF technique has been applied during three RV Meteor cruises to approximately 5,000 Late Quaternary sediment samples from altogether 23 gravity cores, 25 multicorer cores and two box cores from the eastern South Atlantic off South Africa/Namibia and the eastern Atlantic off NW Africa.

Dolomite-rich coralline algae in reefs resist dissolution in acidified conditions

Coral reef ecosystems develop best in high-flow environments but their fragile frameworks are also vulnerable to high wave energy. Wave-resistant algal rims, predominantly made up of the crustose coralline algae (CCA) Porolithon onkodes and P. pachydermum, are therefore critical structural elements for the survival of many shallow coral reefs. Concerns are growing about the susceptibility of CCA to ocean acidification because CCA Mg-calcite skeletons are more susceptible to dissolution under low pH conditions than coral aragonite skeletons. However, the recent discovery of dolomite (Mg0.5Ca0.5(CO3)), a stable carbonate, in P. onkodes cells necessitates a reappraisal of the impacts of ocean acidification on these CCA. Here we show, using a dissolution experiment, that dried dolomite-rich CCA have 6-10 times lower rates of dissolution than predominantly Mg-calcite CCA in both high-CO2 (~ 700 ppm) and control (~ 380 ppm) environments, respectively. We reveal this stabilizing mechanism to be a combination of reduced porosity due to dolomite infilling and selective dissolution of other carbonate minerals. Physical break-up proceeds by dissolution of Mg-calcite walls until the dolomitized cell eventually drops out intact. Dolomite-rich CCA frameworks are common in shallow coral reefs globally and our results suggest that it is likely that they will continue to provide protection and stability for coral reef frameworks as CO2 rises.

Ground-penetrating radar (GPR) point measurements of ice thickness in Austria

Glacier thickness is an important factor in the course of glacier retreat in a warming climate. Thiese study data presents the results (point data) of GPR surveys on 66 Austrian mountain glaciers carried out between 1995 and 2014. The glacier areas range from 0.001 to 18.4 km**2, and their ice thickness has been surveyed with an average density of 36 points/km**2 . The glacier areas and surface elevations refer to the second Austrian glacier inventory (mapped between 1996 and 2002). According to the glacier state recorded in the second glacier inventory, the 64 glaciers cover an area of 223.3±3.6 km**3. Maps of glacier thickness have been calculated by Fischer and Kuhn (2013) with a mean thickness of 50±3 m and contain an glacier volume of 11.9±1.1 km**3. The mean maximum ice thickness is 119±5 m. The ice thickness measurements have been carried out with the transmitter of Narod and Clarke (1994) combined with restively loaded dipole antennas (Wu and King, 1965; Rose and Vickers, 1974) at central wavelengths of 6.5 (30 m antenna length) and 4.0 MHz (50 m antenna length). The signal was recorded trace by trace with an oscilloscope. 168 m/µs as used by Haeberli et al. (1982), Bauder (2001), and Narod and Clarke (1994), the signal velocity in air is assumed to be 300 m/µs. Details on the method can be are found in Fischer and Kuhn (2013), as well as Span et al. (2005) and Fischer et al. (2007).

Numerical simulation of the upward propagation of a flame in a vertical tube filled with a very lean mixture.

Upwardpropagation of a premixed flame in averticaltubefilled with a very leanmixture is simulated numerically using a single irreversible Arrhenius reaction model with infinitely high activation energy. In the absence of heat losses and preferential diffusion effects, a curved flame with stationary shape and velocity close to those of an open bubble ascending in the same tube is found for values of the fuel mass fraction above a certain minimum that increases with the radius of the tube, while the numerical computations cease to converge to a stationary solution below this minimum mass fraction. The vortical flow of the gas behind the flame and in its transport region is described for tubes of different radii. It is argued that this flow may become unstable when the fuel mass fraction is decreased, and that this instability, together with the flame stretch due to the strong curvature of the flame tip in narrow tubes, may be responsible for the minimum fuel mass fraction. Radiation losses and a Lewis number of the fuel slightly above unity decrease the final combustion temperature at the flame tip and increase the minimum fuel mass fraction, while a Lewis number slightly below unity has the opposite effect.