Interconnectivity between molecular subtypes and tumor stage in colorectal cancer

BACKGROUND: There are profound individual differences in clinical outcomes between colorectal cancers (CRCs) presenting with identical stage of disease. Molecular stratification, in conjunction with the traditional TNM staging, is a promising way to predict patient outcomes. We investigated the interconnectivity between tumor stage and tumor biology reflected by the Consensus Molecular Subtypes (CMSs) in CRC, and explored the possible value of these insights in patients with stage II colon cancer. METHODS: We performed a retrospective analysis using clinical records and gene expression profiling in a meta-cohort of 1040 CRC patients. The interconnectivity of tumor biology and disease stage was assessed by investigating the association between CMSs and TNM classification. In order to validate the clinical applicability of our findings we employed a meta-cohort of 197 stage II colon cancers. RESULTS: CMS4 was significantly more prevalent in advanced stages of disease (stage I 9.8% versus stage IV 38.5%, p < 0.001). The observed differential gene expression between cancer stages is at least partly explained by the biological differences as reflected by CMS subtypes. Gene signatures for stage III-IV and CMS4 were highly correlated (r = 0.77, p < 0.001). CMS4 cancers showed an increased progression rate to more advanced stages (CMS4 compared to CMS2: 1.25, 95% CI: 1.08-1.46). Patients with a CMS4 cancer had worse survival in the high-risk stage II tumors compared to the total stage II cohort (5-year DFS 41.7% versus 100.0%, p = 0.008). CONCLUSIONS: Considerable interconnectivity between tumor biology and tumor stage in CRC exists. This implies that the TNM stage, in addition to the stage of progression, might also reflect distinct biological disease entities. These insights can potentially be utilized to optimize identification of high-risk stage II colo

Subunit-selective proteasome activity profiling uncovers uncoupled proteasome subunit activities during bacterial infections

The proteasome is a nuclear‐cytoplasmic proteolytic complex involved in nearly all regulatory pathways in plant cells. The three different catalytic activities of the proteasome can have different functions, but tools to monitor and control these subunits selectively are not yet available in plant science. Here, we introduce subunit‐selective inhibitors and dual‐color fluorescent activity‐based probes for studying two of the three active catalytic subunits of the plant proteasome. We validate these tools in two model plants and use this to study the proteasome during plant–microbe interactions. Our data reveal that Nicotiana benthamiana incorporates two different paralogs of each catalytic subunit into active proteasomes. Interestingly, both β1 and β5 activities are significantly increased upon infection with pathogenic Pseudomonas syringae pv. tomato DC3000 lacking hopQ1‐1 [PtoDC3000(ΔhQ)] whilst the activity profile of the β1 subunit changes. Infection with wild‐type PtoDC3000 causes proteasome activities that range from strongly induced β1 and β5 activities to strongly suppressed β5 activities, revealing that β1 and β5 activities can be uncoupled during bacterial infection. These selective probes and inhibitors are now available to the plant science community, and can be widely and easily applied to study the activity and role of the different catalytic subunits of the proteasome in different plant species.Bio-organic Synthesi

Report on anonymous witnesses in the Netherlands

To a large extent, Dutch criminal proceedings take the form of an official inquiry rather than a contest between two parties who are responsible for bringing out the evidence. These proceedings can be characterized as investigations into the material facts by state officials. The inquisitorial nature of such proceedings is expressed in particular by the position of the state officials involved in criminal justice. These officials are responsible for discovering the truth and must therefore remain objective and make an effort to find out whether the accused is guilty of a criminal offence. The trial judge has a central and active role in the process of finding the facts. It should be added that the trial judge not only conducts the investigation at the trial, but also decides on the guilt or innocence of the accused. The Dutch criminal justice system, contrary to a few other civil law countries and the common law countries, has no trial by jury

Test-retest and inter- and intrareliability of the quality of the upper-extremity skills test in preschool-age children with cerebral palsy

OBJECTIVE: To investigate the test-retest, inter-, and intraobserver reliability of the Quality of Upper Extremity Skills Test (QUEST) in young children with cerebral palsy (CP). DESIGN: For test-retest reliability, a test-retest design was used; for the intra- and interobserver reliability, the videotaped test was scored on 2 occasions by 1 observer and by various observers. SETTING: Groups of preschool-age children in 2 general rehabilitation centers. PARTICIPANTS: Twenty-one children with CP (12 boys, 9 girls) aged 2 to 4.5 years (mean, 39 mo). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURE: Spearman correlation coefficient. RESULTS: The data indicated that test-retest reliability was strong (rho range, .85-.94). Intraobserver agreement (rho range, .63-.95) and agreement between various observers (rho range, .72-.90) were moderate to strong. CONCLUSIONS: Test-retest and inter- and intraobserver reliability of the QUEST in preschool-age children with CP is good

Aliskiren inhibits atherosclerosis development and improves plaque stability in APOEM*3Leiden.CETP transgenic mice with or without treatment with atorvastatin

Diabetes mellitus: pathophysiological changes and therap

APOE*3LEIDEN.CETP TRANSGENIC MICE AS MODEL FOR THE METABOLIC SYNDROME

Diabetes mellitus: pathophysiological changes and therap