Comprehensive analysis of CpG island methylator phenotype (CIMP)-high, -low, and -negative colorectal cancers based on protein marker expression and molecular features

CpG island methylator phenotype (CIMP) is being investigated for its role in the molecular and prognostic classification of colorectal cancer patients but is also emerging as a factor with the potential to influence clinical decision-making. We report a comprehensive analysis of clinico-pathological and molecular features (KRAS, BRAF and microsatellite instability, MSI) as well as of selected tumour- and host-related protein markers characterizing CIMP-high (CIMP-H), -low, and -negative colorectal cancers. Immunohistochemical analysis for 48 protein markers and molecular analysis of CIMP (CIMP-H: ? 4/5 methylated genes), MSI (MSI-H: ? 2 instable genes), KRAS, and BRAF were performed on 337 colorectal cancers. Simple and multiple regression analysis and receiver operating characteristic (ROC) curve analysis were performed. CIMP-H was found in 24 cases (7.1%) and linked (p < 0.0001) to more proximal tumour location, BRAF mutation, MSI-H, MGMT methylation (p = 0.022), advanced pT classification (p = 0.03), mucinous histology (p = 0.069), and less frequent KRAS mutation (p = 0.067) compared to CIMP-low or -negative cases. Of the 48 protein markers, decreased levels of RKIP (p = 0.0056), EphB2 (p = 0.0045), CK20 (p = 0.002), and Cdx2 (p < 0.0001) and increased numbers of CD8+ intra-epithelial lymphocytes (p < 0.0001) were related to CIMP-H, independently of MSI status. In addition to the expected clinico-pathological and molecular associations, CIMP-H colorectal cancers are characterized by a loss of protein markers associated with differentiation, and metastasis suppression, and have increased CD8+ T-lymphocytes regardless of MSI status. In particular, Cdx2 loss seems to strongly predict CIMP-H in both microsatellite-stable (MSS) and MSI-H colorectal cancers. Cdx2 is proposed as a surrogate marker for CIMP-H.

The impact of CpG island methylator phenotype and microsatellite instability on tumour budding in colorectal cancer

In colorectal cancer, tumour budding, a process likened to epithelial mesenchymal transition, is an adverse prognostic factor which is rarely found in tumours with high-level microsatellite instability (MSI-H). Cases with MSI-H or high-level CpG island methylator phenotype (CIMP-H) have similar histomorphological features, yet seemingly opposite prognosis. We hypothesized that tumour budding is related to CIMP, thus partially explaining this prognostic difference.

First foot prints of chemistry on the shore of the Island of Superheavy Elements

Chemistry has arrived on the shore of the Island of Stability with the first chemical investigation of the superheavy elements Cn, 113, and 114. The results of three experimental series leading to first measured thermodynamic data and qualitatively evaluated chemical properties for these elements are described. An interesting volatile compound class has been observed in the on-line experiments for the elements Bi and Po. Hence, an exciting chemical study of their heavier transactinide homologues, elements 115 and 116 is suggested.

The VLT/NaCo large program to probe the occurrence of exoplanets and brown dwarfs at wide orbits II. Survey description, results, and performances

Context. Young, nearby stars are ideal targets for direct imaging searches for giant planets and brown dwarf companions. After the first-imaged planet discoveries, vast efforts have been devoted to the statistical analysis of the occurence and orbital distributions of giant planets and brown dwarf companions at wide (>= 5-6 AU) orbits. Aims. In anticipation of the VLT/SPHERE planet-imager, guaranteed-time programs, we have conducted a preparatory survey of 86 stars between 2009 and 2013 to identify new faint comoving companions to ultimately analyze the occurence of giant planets and brown dwarf companions at wide (10-2000 AU) orbits around young, solar-type stars. Methods. We used NaCo at VLT to explore the occurrence rate of giant planets and brown dwarfs between typically 0.1 and 8 ''. Diffraction-limited observations in H-band combined with angular differential imaging enabled us to reach primary star-companion brightness ratios as small as 10(-6) at 1.5 ''. Repeated observations at several epochs enabled us to discriminate comoving companions from background objects. Results. During our survey, twelve systems were resolved as new binaries, including the discovery of a new white dwarf companion to the star HD8049. Around 34 stars, at least one companion candidate was detected in the observed field of view. More than 400 faint sources were detected; 90% of them were in four crowded fields. With the exception of HD8049 B, we did not identify any new comoving companions. The survey also led to spatially resolved images of the thin debris disk around HD61005 that have been published earlier. Finally, considering the survey detection limits, we derive a preliminary upper limit on the frequency of giant planets for the semi-major axes of [10, 2000] AU: typically less than 15% between 100 and 500 AU and less than 10% between 50 and 500 AU for exoplanets that are more massive than 5 M-Jup and 10 M-Jup respectively, if we consider a uniform input distribution and a confidence level of 95%. Conclusions. The results from this survey agree with earlier programs emphasizing that massive, gas giant companions on wide orbits around solar-type stars are rare. These results will be part of a broader analysis of a total of similar to 210 young, solar-type stars to bring further statistical constraints for theoretical models of planetary formation and evolution.