Absent in Melanoma 2 (AIM2) is an important mediator of interferon-dependent and -independent HLA-DRA and HLA-DRB gene expression in colorectal cancers

Absent in Melanoma 2 (AIM2) is a member of the HIN-200 family of hematopoietic, IFN-inducible, nuclear proteins, associated with both, infection defense and tumor pathology. Recently, AIM2 was found to act as a DNA sensor in innate immunity. In addition, we and others have previously demonstrated a high frequency of AIM2-alterations in microsatellite unstable (MSI-H) tumors. To further elucidate AIM2 function in colorectal tumors, we here addressed AIM2-responsive target genes by microarray based gene expression profiling of 22 244 human genes. A total of 111 transcripts were significantly upregulated, whereas 80 transcripts turned out to be significantly downregulated in HCT116 cells, constitutively expressing AIM2, compared with AIM2-negative cells. Among the upregulated genes that were validated by quantitative PCR and western blotting we recognized several interferon-stimulated genes (ISGs: IFIT1, IFIT2, IFIT3, IFI6, IRF7, ISG15, HLA-DRA, HLA-DRB, TLR3 and CIITA), as well as genes involved in intercellular adhesion and matrix remodeling. Expression of ISGs correlated with expression of AIM2 in 10 different IFN-γ treated colorectal cancer cell lines. Moreover, small interfering RNA-mediated knock-down of AIM2 resulted in reduced expression of HLA-DRA, HLA-DRB and CIITA in IFN-γ-treated cells. IFN-γ independent induction of HLA-DR genes and their encoded proteins was also demonstrated upon doxycyclin-regulated transient induction of AIM2. Luciferase reporter assays revealed induction of the HLA-DR promoter upon AIM2 transfection in different cell lines. STAT-signaling was not involved in IFN-γ independent induction of ISGs, arguing against participation of cytokines released in an autostimulating manner. Our data indicate that AIM2 mediates both IFN-γ dependent and independent induction of several ISGs, including genes encoding the major histocompatibility complex (MHC) class II antigens HLA-DR-α and -β. This suggests a novel role of the IFN/AIM2/ISG cascade likewise in cancer cells

Simulation of Receptivity and Induced Transition From Discrete Roughness Elements

The final publication is available at Springer via http://dx.doi.org/10.1007/s10494-015-9636-yDordrecht Simulations have been carried out to predict the receptivity and growth of crossflow vortices created by Discrete Roughness Elements (DREs) The final transition to turbulence has also been examined, including the effect of DRE spacing and freestream turbulence. Measurements by Hunt and Saric (2011) of perturbation mode shape at various locations were used to validate the code in particular for the receptivity region. The WALE sub-grid stress (SGS) model was adopted for application to transitional flows, since it allows the SGS viscosity to vanish in laminar regions and in the innermost region of the boundary layer when transition begins. Simulations were carried out for two spanwise wavelengths: λ= 12mm (critical) and λ= 6mm (control) and for roughness heights (k) from 12 μm to 42 μm. The base flow considered was an ASU (67)-0315 aerofoil with 45 ⁰ sweep at -2.9 ⁰ incidence and with onset flow at a chord-based Reynolds number Re <inf>c</inf>= 2.4x10 ⁶. For λ= 12mm results showed, in accord with the experimental data, that the disturbance amplitude growth rate was linear for k = 12 μm and 24 μm, but the growth rate was decreased for k = 36 μm Receptivity to λ= 6mm roughness showed equally good agreement with experiments, indicating that this mode disappeared after a short distance to be replaced by a critical wavelength mode. Analysis of the development of modal disturbance amplitudes with downstream distance showed regions of linear, non-linear, saturation, and secondary instability behaviour. Examination of breakdown to turbulence revealed two possible routes: the first was 2D-like transition (probably Tollmien-Schlichting waves even in the presence of crossflow vortices) when transition occurred beyond the pressure minimum; the second was a classical crossflow vortex secondary instability, leading to the formation of a turbulent wedge

Concerted down-regulation of immune-system related genes predicts metastasis in colorectal carcinoma

BACKGROUND: This study aimed at the identification of prognostic gene expression markers in early primary colorectal carcinomas without metastasis at the time point of surgery by analyzing genome-wide gene expression profiles using oligonucleotide microarrays. METHODS: Cryo-conserved tumor specimens from 45 patients with early colorectal cancers were examined, with the majority of them being UICC stage II or earlier and with a follow-up time of 41-115 months. Gene expression profiling was performed using Whole Human Genome 4x44K Oligonucleotide Microarrays. Validation of microarray data was performed on five of the genes in a smaller cohort. RESULTS: Using a novel algorithm based on the recursive application of support vector machines (SVMs), we selected a signature of 44 probes that discriminated between patients developing later metastasis and patients with a good prognosis. Interestingly, almost half of the genes was related to the patients' immune response and showed reduced expression in the metastatic cases. CONCLUSIONS: Whereas up to now gene signatures containing genes with various biological functions have been described for prediction of metastasis in CRC, in this study metastasis could be well predicted by a set of gene expression markers consisting exclusively of genes related to the MHC class II complex involved in immune response. Thus, our data emphasize that the proper function of a comprehensive network of immune response genes is of vital importance for the survival of colorectal cancer patients