Mining tissue microarray data to uncover combinations of biomarker expression patterns that improve intermediate staging and grading of clear cell renal cell cancer

PURPOSE: Tumor stage and nuclear grade are the most important prognostic parameters of clear cell renal cell carcinoma (ccRCC). The progression risk of ccRCC remains difficult to predict particularly for tumors with organ-confined stage and intermediate differentiation grade. Elucidating molecular pathways deregulated in ccRCC may point to novel prognostic parameters that facilitate planning of therapeutic approaches. EXPERIMENTAL DESIGN: Using tissue microarrays, expression patterns of 15 different proteins were evaluated in over 800 ccRCC patients to analyze pathways reported to be physiologically controlled by the tumor suppressors von Hippel-Lindau protein and phosphatase and tensin homologue (PTEN). Tumor staging and grading were improved by performing variable selection using Cox regression and a recursive bootstrap elimination scheme. RESULTS: Patients with pT2 and pT3 tumors that were p27 and CAIX positive had a better outcome than those with all remaining marker combinations. A prolonged survival among patients with intermediate grade (grade 2) correlated with both nuclear p27 and cytoplasmic PTEN expression, as well as with inactive, nonphosphorylated ribosomal protein S6. By applying graphical log-linear modeling for over 700 ccRCC for which the molecular parameters were available, only a weak conditional dependence existed between the expression of p27, PTEN, CAIX, and p-S6, suggesting that the dysregulation of several independent pathways are crucial for tumor progression. CONCLUSIONS: The use of recursive bootstrap elimination, as well as graphical log-linear modeling for comprehensive tissue microarray (TMA) data analysis allows the unraveling of complex molecular contexts and may improve predictive evaluations for patients with advanced renal cancer.

Homeopathic Preparations of Quartz, Sulfur and Copper Sulfate Assessed by UV-Spectroscopy

Homeopathic preparations are used in homeopathy and anthroposophic medicine. Although there is evidence of effectiveness in several clinical studies, including double-blinded randomized controlled trials, their nature and mode of action could not be explained with current scientific approaches yet. Several physical methods have already been applied to investigate homeopathic preparations but it is yet unclear which methods are best suited to identify characteristic physicochemical properties of homeopathic preparations. The aim of this study was to investigate homeopathic preparations with UV-spectroscopy. In a blinded, randomized, controlled experiment homeopathic preparations of copper sulfate (CuSO(4); 11c-30c), quartz (SiO(2); 10c-30c, i.e., centesimal dilution steps) and sulfur (S; 11×-30×, i.e., decimal dilution steps) and controls (one-time succussed diluent) were investigated using UV-spectroscopy and tested for contamination by inductively coupled plasma mass spectrometry (ICP-MS). The UV transmission for homeopathic preparations of CuSO(4) preparations was significantly lower than in controls. The transmission seemed to be also lower for both SiO(2) and S, but not significant. The mean effect size (95% confidence interval) was similar for the homeopathic preparations: CuSO(4) (pooled data) 0.0544% (0.0260-0.0827%), SiO(2) 0.0323% (-0.0064% to 0.0710%) and S 0.0281% (-0.0520% to 0.1082%). UV transmission values of homeopathic preparations had a significantly higher variability compared to controls. In none of the samples the concentration of any element analyzed by ICP-MS exceeded 100 ppb. Lower transmission of UV light may indicate that homeopathic preparations are less structured or more dynamic than their succussed pure solvent.

Ion fractionation in young sea ice from Kongsfjorden, Svalbard

The fractionation of major sea-water ions, or deviation in their relative concentrations from Standard Mean Ocean Water ratios, has been frequently observed in sea ice. It is generally thought to be associated with precipitation of solid salts at certain eutectic temperatures. The variability found in bulk sea-ice samples indicates that the fractionation of ions depends on the often unknown thermal history of sea ice, which affects the structure of pore networks and fate of solid salts within them. Here we investigate the distribution of ions in Arctic sea ice that is a few weeks old with a reconstructible thermal history. We separate the centrifugable (interconnected) and entrapped (likely disconnected) contributions to the ice salinity and determine their ion fractionation signatures. The results indicate that differential diffusion of ions, rather than eutectic precipitation of cryohydrates, has led to significant ion fractionation. The finding emphasizes the role of coupled diffusive–convective salt transport through complex pore networks in shaping the biogeochemistry of sea ice.

210Pb dating of the Miaoergou ice core from the eastern Tien Shan, China

In 2005, two ice cores with lengths of 58.7 and 57.6 m respectively to bedrock were recovered from the Miaoergou flat-topped glacier (43 degrees 03 ' 19 '' N, 94 degrees 19 ' 21 '' E; 4512 m a.s.l.), eastern Tien Shan. Pb-210 dating of one of the ice cores (57.6 m) was performed, and an age of AD 1851 +/- 6 at a depth of 35.2 m w.e. was determined. For the period AD 1851-2005, a mean annual net accumulation of 229 +/- 7 mm w.e. a(-1) was calculated. At the nearby oasis city of Hami (similar to 80 km from the Miaoergou flat-topped glacier) the annual precipitation rate is 38 mm w.e. a(-1), hence glacial meltwater is a major water supply for local residents. The surface activity concentration of Pb-210(ex) was found to be similar to 400 mBq kg(-1), which is higher than observed at other continental sites such as Belukha, Russia, and Tsambagarav, Mongolia, which have surface activity concentrations of 280 mBq kg(-1). The Pb-210 dating agrees well with the chronological sequence deduced from the annual-layer counting resulting from the seasonalities of delta O-18 and trace metals for the period AD 1953-2005, and beta-activity horizons resulting from atmospheric nuclear testing during the period AD 1962-63. We conclude that Pb-210 analysis is a suitable method for obtaining a continuous dating of the Miaoergou ice core for similar to 160 years, which can also be applied to other ice cores recovered from the mountains of western China.

RADIX: a minimal-resources rapid-access drilling system

Determining the expected age at a potential ice-core drilling site on a polar ice sheet generally depends on a combination of information from remote-sensing methods, estimates of current accumulation and modelling. This poses irreducible uncertainties in retrieving an undisturbed ice core of the desired age. Although recently perfected radar techniques will improve the picture of the ice sheet below future drilling sites, rapid prospective drillings could further increase the success of deep drilling projects. Here we design and explore a drilling system for a minimum-size rapid-access hole. The advantages of a small hole are the low demand for drilling fluid, low overall weight of the equipment, fast installing and de-installing and low costs. We show that, in theory, drilling of a 20mm hole to a depth of 3000m is possible in ~4 days. First concepts have been realized and verified in the field. Both the drill cuttings and the hole itself can be used to characterize the properties of the ice sheet and its potential to provide a trustworthy palaeo-record. A candidate drilling site could be explored in ~2 weeks, which would enable the characterization of several sites in one summer season.

Reliability of operational data from pig herds and performance ratings by veterinarians and pig farmers collected during telephone interviews for the evaluation of a PCV2 piglet vaccination

BackgroundThe aim of the present study was to evaluate the feasibility of using a telephone survey in gaining an understanding of the possible herd and management factors influencing the performance (i.e. safety and efficacy) of a vaccine against porcine circovirus type 2 (PCV2) in a large number of herds and to estimate customers¿ satisfaction.ResultsDatasets from 227 pig herds that currently applied or have applied a PCV2 vaccine were analysed. Since 1-, 2- and 3-site production systems were surveyed, the herds were allocated in one of two subsets, where only applicable variables out of 180 were analysed. Group 1 was comprised of herds with sows, suckling pigs and nursery pigs, whereas herds in Group 2 in all cases kept fattening pigs. Overall 14 variables evaluating the subjective satisfaction with one particular PCV2 vaccine were comingled to an abstract dependent variable for further models, which was characterized by a binary outcome from a cluster analysis: good/excellent satisfaction (green cluster) and moderate satisfaction (red cluster). The other 166 variables comprised information about diagnostics, vaccination, housing, management, were considered as independent variables. In Group 1, herds using the vaccine due to recognised PCV2 related health problems (wasting, mortality or porcine dermatitis and nephropathy syndrome) had a 2.4-fold increased chance (1/OR) of belonging to the green cluster. In the final model for Group 1, the diagnosis of diseases other than PCV2, the reason for vaccine administration being other than PCV2-associated diseases and using a single injection of iron had significant influence on allocating into the green cluster (P¿<¿0.05). In Group 2, only unchanged time or delay of time of vaccination influenced the satisfaction (P¿<¿0.05).ConclusionThe methodology and statistical approach used in this study were feasible to scientifically assess ¿satisfaction¿, and to determine factors influencing farmers¿ and vets¿ opinion about the safety and efficacy of a new vaccine.

The EPICA Dronning Maud Land deep drilling operation

We report on the EPICA Dronning Maud Land (East Antarctica) deep drilling operation. Starting with the scientific questions that led to the outline of the EPICA project, we introduce the setting of sister drillings at NorthGRIP and EPICA Dome C within the European ice-coring community. The progress of the drilling operation is described within the context of three parallel, deep-drilling operations, the problems that occurred and the solutions we developed. Modified procedures are described, such as the monitoring of penetration rate via cable weight rather than motor torque, and modifications to the system (e.g. closing the openings at the lower end of the outer barrel to reduce the risk of immersing the drill in highly concentrated chip suspension). Parameters of the drilling (e.g. core-break force, cutter pitch, chips balance, liquid level, core production rate and piece number) are discussed. We also review the operational mode, particularly in the context of achieved core length and piece length, which have to be optimized for drilling efficiency and core quality respectively. We conclude with recommendations addressing the design of the chip-collection openings and strictly limiting the cable-load drop with respect to the load at the start of the run.

Drilling into debris-rich basal ice at the bottom of the NEEM (Greenland) borehole

After the NEEM (Greenland) deep ice-core drilling was declared terminated with respect to developing stratigraphic climate reconstructions, efforts were turned toward collecting basal ice-sheet debris and, if possible, drilling into the bedrock itself. In 2010, several meters of banded debris-rich ice were obtained under normal ice-drilling operations with the NEEM version of the Hans Tausen (HT) drill, but further penetration was obstructed by a rock in the path of the drill head at 2537.36 m. During short campaigns in 2011 and 2012, attempts were made to penetrate further using various reinforced ice cutters mounted on the HT drill head, tailored to cut through rock. These had some success in penetrating coarse material, but produced severely damaged cutters. Additionally a 51 mm diameter diamond cutting tipped rock drill was adapted to fit the NEEM drill. With this device, several additional meters of core containing subglacial sediments, rocks and rock fragments were collected. With these tools 1.39 m of additional material were obtained during the 2011 field season, and 7.1 m during 2012. Subglacial water refreezing into the newly formed borehole hindered further penetration, and the bedrock interface was not reached before final closure of the NEEM Camp.