Gene expression patterns unveil a new level of molecular heterogeneity in colorectal cancer.

The recognition that colorectal cancer (CRC) is a heterogeneous disease in terms of clinical behaviour and response to therapy translates into an urgent need for robust molecular disease subclassifiers that can explain this heterogeneity beyond current parameters (MSI, KRAS, BRAF). Attempts to fill this gap are emerging. The Cancer Genome Atlas (TGCA) reported two main CRC groups, based on the incidence and spectrum of mutated genes, and another paper reported an EMT expression signature defined subgroup. We performed a prior free analysis of CRC heterogeneity on 1113 CRC gene expression profiles and confronted our findings to established molecular determinants and clinical, histopathological and survival data. Unsupervised clustering based on gene modules allowed us to distinguish at least five different gene expression CRC subtypes, which we call surface crypt-like, lower crypt-like, CIMP-H-like, mesenchymal and mixed. A gene set enrichment analysis combined with literature search of gene module members identified distinct biological motifs in different subtypes. The subtypes, which were not derived based on outcome, nonetheless showed differences in prognosis. Known gene copy number variations and mutations in key cancer-associated genes differed between subtypes, but the subtypes provided molecular information beyond that contained in these variables. Morphological features significantly differed between subtypes. The objective existence of the subtypes and their clinical and molecular characteristics were validated in an independent set of 720 CRC expression profiles. Our subtypes provide a novel perspective on the heterogeneity of CRC. The proposed subtypes should be further explored retrospectively on existing clinical trial datasets and, when sufficiently robust, be prospectively assessed for clinical relevance in terms of prognosis and treatment response predictive capacity. Original microarray data were uploaded to the ArrayExpress database (http://www.ebi.ac.uk/arrayexpress/) under Accession Nos E-MTAB-990 and E-MTAB-1026. © 2013 Swiss Institute of Bioinformatics. Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland

Dissecting the knee - Air shower measurements with KASCADE

Recent results of the KASCADE air shower experiment are presented in order to shed some light on the astrophysics of cosmic rays in the region of the knee in the energy spectrum. The results include investigations of high-energy interactions in the atmosphere, the analysis of the arrival directions of cosmic rays, the determination of the mean logarithmic mass, and the unfolding of energy spectra for elemental groups

Ab-initio calculation of the 6Li{}^6Li binding energy with the Hybrid Multideterminant scheme

We perform an ab-initio calculation for the binding energy of ${}^6Li$ using the CD-Bonn 2000 NN potential renormalized with the Lee-Suzuki method. The many-body approach to the problem is the Hybrid Multideterminant method. The results indicate a binding energy of about $31 MeV$, within a few hundreds KeV uncertainty. The center of mass diagnostics are also discussed.Comment: 18 pages with 3 figures. More calculations added, to be published in EPJ

KASCADE: Astrophysical results and tests of hadronic interaction models

KASCADE is a multi-detector setup to get redundant information on single air shower basis. The information is used to perform multiparameter analyses to solve the threefold problem of the reconstruction of (i)the unknown primary energy, (ii) the primary mass, and (iii) to quantify the characteristics of the hadronic interactions in the air-shower development. In this talk recent results of the KASCADE data analyses are summarized concerning cosmic ray anisotropy studies, determination of flux spectra for different primary mass groups, and approaches to test hadronic interaction models. Neither large scale anisotropies nor point sources were found in the KASCADE data set. The energy spectra of the light element groups result in a knee-like bending and a steepening above the knee. The topology of the individual knee positions shows a dependency on the primary particle. Though no hadronic interaction model is fully able to describe the multi-parameter data of KASCADE consistently, the more recent models or improved versions of older models reproduce the data better than few years ago.Comment: to appear in Nucl. Phys. B (Proc. Suppl.), Proc. of the XIII ISVHECRI, Pylos 2004 - with a better quality of the figure

The KASCADE-Grande Experiment and the LOPES Project

KASCADE-Grande is the extension of the multi-detector setup KASCADE to cover a primary cosmic ray energy range from 100 TeV to 1 EeV. The enlarged EAS experiment provides comprehensive observations of cosmic rays in the energy region around the knee. Grande is an array of 700 x 700 sqm equipped with 37 plastic scintillator stations sensitive to measure energy deposits and arrival times of air shower particles. LOPES is a small radio antenna array to operate in conjunction with KASCADE-Grande in order to calibrate the radio emission from cosmic ray air showers. Status and capabilities of the KASCADE-Grande experiment and the LOPES project are presented.Comment: To appear in Nuclear Physics B, Proceedings Supplements, as part of the volume for the CRIS 2004, Cosmic Ray International Seminar: GZK and Surrounding

Radio detection of cosmic ray air showers with LOPES

In the last few years, radio detection of cosmic ray air showers has experienced a true renaissance, becoming manifest in a number of new experiments and simulation efforts. In particular, the LOPES project has successfully implemented modern interferometric methods to measure the radio emission from extensive air showers. LOPES has confirmed that the emission is coherent and of geomagnetic origin, as expected by the geosynchrotron mechanism, and has demonstrated that a large scale application of the radio technique has great potential to complement current measurements of ultra-high energy cosmic rays. We describe the current status, most recent results and open questions regarding radio detection of cosmic rays and give an overview of ongoing research and development for an application of the radio technique in the framework of the Pierre Auger Observatory.Comment: 8 pages; Proceedings of the CRIS2006 conference, Catania, Italy; to be published in Nuclear Physics B, Proceedings Supplement

Dual action antifungal small molecule modulates multidrug efflux and TOR signaling.

There is an urgent need for new strategies to treat invasive fungal infections, which are a leading cause of human mortality. Here, we establish two activities of the natural product beauvericin, which potentiates the activity of the most widely deployed class of antifungal against the leading human fungal pathogens, blocks the emergence of drug resistance, and renders antifungal-resistant pathogens responsive to treatment in mammalian infection models. Harnessing genome sequencing of beauvericin-resistant mutants, affinity purification of a biotinylated beauvericin analog, and biochemical and genetic assays reveals that beauvericin blocks multidrug efflux and inhibits the global regulator TORC1 kinase, thereby activating the protein kinase CK2 and inhibiting the molecular chaperone Hsp90. Substitutions in the multidrug transporter Pdr5 that enable beauvericin efflux impair antifungal efflux, thereby impeding resistance to the drug combination. Thus, dual targeting of multidrug efflux and TOR signaling provides a powerful, broadly effective therapeutic strategy for treating fungal infectious disease that evades resistance

Test of four colon cancer risk-scores in formalin fixed paraffin embedded microarray gene expression data.

BACKGROUND: Prognosis prediction for resected primary colon cancer is based on the T-stage Node Metastasis (TNM) staging system. We investigated if four well-documented gene expression risk scores can improve patient stratification. METHODS: Microarray-based versions of risk-scores were applied to a large independent cohort of 688 stage II/III tumors from the PETACC-3 trial. Prognostic value for relapse-free survival (RFS), survival after relapse (SAR), and overall survival (OS) was assessed by regression analysis. To assess improvement over a reference, prognostic model was assessed with the area under curve (AUC) of receiver operating characteristic (ROC) curves. All statistical tests were two-sided, except the AUC increase. RESULTS: All four risk scores (RSs) showed a statistically significant association (single-test, P < .0167) with OS or RFS in univariate models, but with HRs below 1.38 per interquartile range. Three scores were predictors of shorter RFS, one of shorter SAR. Each RS could only marginally improve an RFS or OS model with the known factors T-stage, N-stage, and microsatellite instability (MSI) status (AUC gains < 0.025 units). The pairwise interscore discordance was never high (maximal Spearman correlation = 0.563) A combined score showed a trend to higher prognostic value and higher AUC increase for OS (HR = 1.74, 95% confidence interval [CI] = 1.44 to 2.10, P < .001, AUC from 0.6918 to 0.7321) and RFS (HR = 1.56, 95% CI = 1.33 to 1.84, P < .001, AUC from 0.6723 to 0.6945) than any single score. CONCLUSIONS: The four tested gene expression-based risk scores provide prognostic information but contribute only marginally to improving models based on established risk factors. A combination of the risk scores might provide more robust information. Predictors of RFS and SAR might need to be different