Robust Selection of Cancer Survival Signatures from High-Throughput Genomic Data Using Two-Fold Subsampling

Identifying relevant signatures for clinical patient outcome is a fundamental task in high-throughput studies. Signatures, composed of features such as mRNAs, miRNAs, SNPs or other molecular variables, are often non-overlapping, even though they have been identified from similar experiments considering samples with the same type of disease. The lack of a consensus is mostly due to the fact that sample sizes are far smaller than the numbers of candidate features to be considered, and therefore signature selection suffers from large variation. We propose a robust signature selection method that enhances the selection stability of penalized regression algorithms for predicting survival risk. Our method is based on an aggregation of multiple, possibly unstable, signatures obtained with the preconditioned lasso algorithm applied to random (internal) subsamples of a given cohort data, where the aggregated signature is shrunken by a simple thresholding strategy. The resulting method, RS-PL, is conceptually simple and easy to apply, relying on parameters automatically tuned by cross validation. Robust signature selection using RS-PL operates within an (external) subsampling framework to estimate the selection probabilities of features in multiple trials of RS-PL. These probabilities are used for identifying reliable features to be included in a signature. Our method was evaluated on microarray data sets from neuroblastoma, lung adenocarcinoma, and breast cancer patients, extracting robust and relevant signatures for predicting survival risk. Signatures obtained by our method achieved high prediction performance and robustness, consistently over the three data sets. Genes with high selection probability in our robust signatures have been reported as cancer-relevant. The ordering of predictor coefficients associated with signatures was well-preserved across multiple trials of RS-PL, demonstrating the capability of our method for identifying a transferable consensus signature. The software is available as an R package rsig at CRAN (http://cran.r-project.org).     

Resistance to Erythropoiesis Stimulating Agents in Patients Treated with Online Hemodiafiltration and Ultrapure Low-Flux Hemodialysis: Results from a Randomized Controlled Trial (CONTRAST)

Resistance to erythropoiesis stimulating agents (ESA) is common in patients undergoing chronic hemodialysis (HD) treatment. ESA responsiveness might be improved by enhanced clearance of uremic toxins of middle molecular weight, as can be obtained by hemodiafiltration (HDF). In this analysis of the randomized controlled CONvective TRAnsport STudy (CONTRAST; {"type":"clinical-trial","attrs":{"text":"NCT00205556","term_id":"NCT00205556"}}NCT00205556), the effect of online HDF on ESA resistance and iron parameters was studied. This was a pre-specified secondary endpoint of the main trial. A 12 months'' analysis of 714 patients randomized to either treatment with online post-dilution HDF or continuation of low-flux HD was performed. Both groups were treated with ultrapure dialysis fluids. ESA resistance, measured every three months, was expressed as the ESA index (weight adjusted weekly ESA dose in daily defined doses [DDD]/hematocrit). The mean ESA index during 12 months was not different between patients treated with HDF or HD (mean difference HDF versus HD over time 0.029 DDD/kg/Hct/week [−0.024 to 0.081]; P = 0.29). Mean transferrin saturation ratio and ferritin levels during the study tended to be lower in patients treated with HDF (−2.52% [−4.72 to −0.31]; P = 0.02 and −49 ng/mL [−103 to 4]; P = 0.06 respectively), although there was a trend for those patients to receive slightly more iron supplementation (7.1 mg/week [−0.4 to 14.5]; P = 0.06).In conclusion, compared to low-flux HD with ultrapure dialysis fluid, treatment with online HDF did not result in a decrease in ESA resistance.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00205556","term_id":"NCT00205556"}}NCT00205556     

No evidence for consistent long‐term growth stimulation of 13 tropical tree species: results from tree‐ring analysis

The important role of tropical forests in the global carbon cycle makes it imperative to assess changes in their carbon dynamics for accurate projections of future climate–vegetation feedbacks. Forest monitoring studies conducted over the past decades have found evidence for both increasing and decreasing growth rates of tropical forest trees. The limited duration of these studies restrained analyses to decadal scales, and it is still unclear whether growth changes occurred over longer time scales, as would be expected if CO₂‐fertilization stimulated tree growth. Furthermore, studies have so far dealt with changes in biomass gain at forest‐stand level, but insights into species‐specific growth changes – that ultimately determine community‐level responses – are lacking. Here, we analyse species‐specific growth changes on a centennial scale, using growth data from tree‐ring analysis for 13 tree species (~1300 trees), from three sites distributed across the tropics. We used an established (regional curve standardization) and a new (size‐class isolation) growth‐trend detection method and explicitly assessed the influence of biases on the trend detection. In addition, we assessed whether aggregated trends were present within and across study sites. We found evidence for decreasing growth rates over time for 8–10 species, whereas increases were noted for two species and one showed no trend. Additionally, we found evidence for weak aggregated growth decreases at the site in Thailand and when analysing all sites simultaneously. The observed growth reductions suggest deteriorating growth conditions, perhaps due to warming. However, other causes cannot be excluded, such as recovery from large‐scale disturbances or changing forest dynamics. Our findings contrast growth patterns that would be expected if elevated CO₂ would stimulate tree growth. These results suggest that commonly assumed growth increases of tropical forests may not occur, which could lead to erroneous predictions of carbon dynamics of tropical forest under climate change.     

Impact of metal pollution on fungal diversity and community structures

The impact of metal pollution on plant communities has been studied extensively in the past, but little is known about the effects of metal pollution on fungal communities that occur in metal‐polluted soils. Metal‐tolerant ecotypes of the ectomycorrhizal fungus Suillus luteus are frequently found in pioneer pine forests in the Campine region in Belgium on metal‐polluted soils. We hypothesized that metal pollution would play an important role in shaping below‐ground fungal communities that occur in these soils and that Suillus luteus would be a dominant player. To test these hypotheses, the fungal communities in a young pine plantation in soil polluted with zinc, and cadmium were studied using 454 amplicon pyrosequencing. Results show that zinc, cadmium and soil organic matter content were strongly correlated with the fungal community composition, but no effects on fungal diversity were observed. As hypothesized, S. luteus was found to be a dominant member of the studied fungal communities. However, other dominant fungal species, such as Sistotrema sp., Wilcoxina mikolae and Cadophora finlandica were found as well. Their presence in metal‐polluted sites is discussed.     

ATP inhibits hydroxyl radical formation and the inflammatory response of stimulated whole blood even under circumstances of severe oxidative stress

We recently reported that Adenosine-5′-triphosphate (ATP) is able to inhibit the inflammatory reaction in stimulated whole blood. Many diseases, in which inflammatory reactions are involved, are associated with oxidative stress. In the present study, we therefore, investigated the effect of ATP on cytokine release in stimulated whole blood under conditions of oxidative stress, as simulated by pre-incubation of blood with hydrogen peroxide (H₂O₂). In the presence of H₂O₂, ATP at concentrations of 100 and 300 μM inhibited Tumour Necrosis factor-alpha (TNF-α) release and stimulated IL-10 release in LPS-PHA stimulated whole blood. Moreover, electron spin resonance (ESR) measurements showed that ATP and its breakdown product Adenosine-5′-diphosphate (ADP) attenuated spin trap-hydroxyl radical adduct formation in the Fenton reaction. Our results demonstrate that even in circumstances of severe oxidative stress, ATP has marked anti-inflammatory properties in stimulated whole blood. Moreover, the inhibition of the hydroxyl radical ESR signal indicates a direct attenuation of oxidative stress by ATP.     

Synthesis and characterization of a hemoglobin-ribavirin conjugate for targeted drug delivery

A novel conjugate of human hemoglobin (Hb) and the nucleoside analogue ribavirin (RBV) was synthesized to demonstrate the utility of Hb as a biocompatible drug carrier for improved drug delivery in the treatment of liver disease. RBV is used in combination with interferon for the treatment of hepatitis C, but its side effects can result in dose limitation or discontinuation of treatment. Targeted delivery of RBV may help to prevent or minimize its toxicity. The hemoglobin-ribavirin conjugate (Hb-RBV) was designed to release bioactive drug upon endocytosis by cells and tissues involved in extracellular Hb catabolism and clearance. Ribavirin-5'-monophosphate (RBV-P) was prepared from RBV and activated as the 5'-monophosphorimidazolide (RBV-P-Im) for reaction with carbonmonoxyhemoglobin to yield Hb-RBV consisting of multiple RBV drugs covalently attached as physiologically labile phosphoramidates via their 5'-hydroxyl groups. A molar drug ratio of six to eight RBV molecules per Hb tetramer was obtained with near complete haptoglobin (Hp) binding of the drug modified Hb maintained. The conjugate complex (Hp-Hb-RBV) was selectively taken up in vitro by cells that express the hemoglobin-haptoglobin receptor, CD163. Recovered ribavirin enzymatically cleaved from Hb-RBV showed equipotent antiproliferative activity compared to control unconjugated RBV against human HepG2 and mouse AML12 liver cell lines. Based upon the reported high level of Hb uptake in the liver, Hb-RBV may be useful in the treatment of certain liver diseases, as well as inflammatory disorders associated with CD163-positive macrophages.     

The influence of landscape and environmental factors on ranavirus epidemiology in a California amphibian assemblage

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An effective method for ecosystem‐scale manipulation of bird abundance and species richness

Manipulation experiments are a cornerstone of ecological research, but can be logistically challenging to execute—particularly when they are intended to isolate the ecological role of large, vagile species, like birds. Despite indirect evidence that birds are influential in many ecosystems, large‐scale, multi‐year bird manipulation experiments are rare. When these studies are conducted, they are typically realized with caged or netted exclosures, an approach that can be expensive, risky for wildlife, and difficult to maintain. In cases where caged exclosures are not appropriate, alternate approaches are needed to allow rigorous empirical studies on the ecological role of birds. Here, we present and validate a method for experimentally increasing the abundance and richness of birds at the scale of entire aquatic ecosystems. Unlike bird exclusion, this approach is experimentally tractable, appealing to land managers, and possible to deploy over large spatial scales. We tested the efficacy of our approach for increasing bird abundance and species richness at 16 central California ponds. Based on bird visitation data obtained by summer camera trapping, our approach significantly increased bird species richness and abundance at manipulated ponds compared to control ponds. Attractant treatments mitigated the negative effects of a major drought on bird species richness and generated a near doubling of bird abundance in the presence of attractants. Treatments had no effect on most mammal species, with the exception of ground squirrels, which increased in abundance in the presence of attractants. These results suggest that attractants are effective in increasing bird abundance and richness. We encourage researchers to consider this approach for experimentally isolating the ecological role of birds in aquatic and open terrestrial ecosystems, especially in cases where cost or logistical constraints preclude the use of caged or netted exclosures.