Predicting School Grades: Can Conscientiousness Compensate for Intelligence?

Intelligence and noncognitive factors such as conscientiousness are strongly related to academic performance. As theory and research differ with respect to their interplay in predicting performance, the present study examines whether conscientiousness compensates for intelligence or enhances the effect of intelligence on performance in 3775 13th grade students from Germany. Latent moderation analyses show positive main effects of intelligence and conscientiousness on grades. Further, analyses reveal synergistic interactions in predicting grades in biology, mathematics, and German, but no interaction in predicting grades in English. Intelligence and grades are more strongly linked if students are conscientious. Multigroup models detected gender differences in biology, but no differences with respect to SES. In biology, conscientiousness has especially strong effects in intelligent men. Conscientiousness thus enhances the effect of intelligence on performance in several subjects.

PPARγ-activation increases intestinal M1 macrophages and mitigates formation of serrated adenomas in mutant KRAS mice.

To identify novel hubs for cancer immunotherapy, we generated C57BL/6J mice with concomitant deletion of the drugable transcription factor PPARγ and transgenic overexpression of the mutant KRASG12V oncogene in enterocytes. Animals developed epithelial hyperplasia, transmural inflammation and serrated adenomas in the small intestine with infiltration of CD3+ FOXP3+ T-cells and macrophages into the lamina propria of the non-malignant mucosa. Within serrated polyps, CD3+ CD8+ T-cells and phosphorylated ERK1/2 were reduced and the senescence marker P21 and macrophage counts up-regulated, indicative of an immunosuppressive tissue microenvironment. Treatment of mutant KRASG12V mice with the PPARγ-agonist rosiglitazone augmented M1 macrophage numbers, reduced IL4 expression and diminished polyp load in mice. Rosiglitazone also promoted M1 polarisation of human THP1-derived macrophages and decreased Il4 mRNA in isolated murine lymphocytes. Thus, inhibition of the oncogenic driver mutant RAS by PPARγ in epithelial and immune cell compartments may be a future target for the prevention or treatment of human malignancies associated with intestinal inflammation.

Myotubularin-related protein 7 inhibits insulin signaling in colorectal cancer.

Phosphoinositide (PIP) phosphatases such as myotubularins (MTMs) inhibit growth factor receptor signaling. However, the function of myotubularin-related protein 7 (MTMR7) in cancer is unknown. We show that MTMR7 protein was down-regulated with increasing tumor grade (G), size (T) and stage (UICC) in patients with colorectal cancer (CRC) (n=1786). The presence of MTMR7 in the stroma correlated with poor prognosis, whereas MTMR7 expression in the tumor was not predictive for patients' survival. Insulin reduced MTMR7 protein levels in human CRC cell lines, and CRC patients with type 2 diabetes mellitus (T2DM) or loss of imprinting (LOI) of insulin-like growth factor 2 (IGF2) had an increased risk for MTMR7 loss. Mechanistically, MTMR7 lowered PIPs and inhibited insulin-mediated AKT-ERK1/2 signaling and proliferation in human CRC cell lines. MTMR7 provides a novel link between growth factor signaling and cancer, and may thus constitute a potential marker or drug target for human CRC.

Subcellular compartmentalization of docking protein-1 contributes to progression in colorectal cancer.

Full-length (FL) docking protein-1 (DOK1) is an adapter protein which inhibits growth factor and immune response pathways in normal tissues, but is frequently lost in human cancers. Small DOK1 variants remain in cells of solid tumors and leukemias, albeit, their functions are elusive. To assess the so far unknown role of DOK1 in colorectal cancer (CRC), we generated DOK1 mutants which mimic the domain structure and subcellular distribution of DOK1 protein variants in leukemia patients. We found that cytoplasmic DOK1 activated peroxisome-proliferator-activated-receptor-gamma (PPARγ) resulting in inhibition of the c-FOS promoter and cell proliferation, whereas nuclear DOK1 was inactive. PPARγ-agonist increased expression of endogenous DOK1 and interaction with PPARγ. Forward translation of this cell-based signaling model predicted compartmentalization of DOK1 in patients. In a large series of CRC patients, loss of DOK1 protein was associated with poor prognosis at early tumor stages (*p=0.001; n=1492). In tumors with cytoplasmic expression of DOK1, survival was improved, whereas nuclear localization of DOK1 correlated with poor outcome, indicating that compartmentalization of DOK1 is critical for CRC progression. Thus, DOK1 was identified as a prognostic factor for non-metastatic CRC, and, via its drugability by PPARγ-agonist, may constitute a potential target for future cancer treatments.

Deficiency of caveolin-1 in Apc(min/+) mice promotes colorectal tumorigenesis.

Caveolin-1 (Cav1), a scaffold protein of membrane caveolae and coactivator of peroxisome proliferator-activated receptor gamma (PPARg), inhibits oncogenic signaling through Ras and wingless. However, the in vivo role of Cav1 in colorectal cancer (CRC) remained unknown. To test whether loss of Cav1 accelerates tumorigenesis, we generated a novel mouse model of CRC by crossing C57BL/6 Apc(min/+) with B6129 Cav1 knockout (Cav1-/-) mice. Apc(min/+) Cav1-/- mice developed large, microinvasive and vascularized intraepithelial adenocarcinomas in the distal colon and rectum with higher incidence than Apc(min/+) Cav1+/- and Apc(min/+) Cav1+/+ littermates. Intratumoral gene signatures related to Ras and wingless signaling were elevated, nuclear localization of PPARg protein and expression of PPARg-target genes were reduced independently of Cav1. The PPARg-agonist rosiglitazone prevented tumor formation in mice irrespectively of the Cav1 status and upregulated expression of the Ras-inhibitory protein docking protein-1. Thus, codeficiency of Cav1 and adenomatous polyposis coli facilitated formation of CRC, and activation of PPARg may offer novel strategies for treatment of CRC.

Pan-histone deacetylase inhibitor panobinostat sensitizes gastric cancer cells to anthracyclines via induction of CITED2.

BACKGROUND & AIMS: Chemotherapy modestly prolongs survival of patients with advanced gastric cancer, but strategies are needed to increase its efficacy. Histone deacetylase (HDAC) inhibitors modify chromatin and can block cancer cell proliferation and promote apoptosis. METHODS: Gastric cancer cell lines were incubated with the HDAC inhibitor LBH589 (Panobinostat, Novartis, Germany); levels of proliferation, apoptosis, histone acetylation, and gene expression were determined. We identified factors downstream of HDAC that regulated chemoresistance. The effects of combination chemotherapy of HDAC inhibitors and anthracyclines were studied in CEA424/SV40 T-antigen (CEA/Tag) transgenic mice, which develop gastric tumors. We analyzed gastric tumor samples from patients using immunohistochemistry. RESULTS: HDAC2 was expressed in human gastric cancer cell lines and tumor samples, as well as in gastric tumors from CEA/Tag mice, compared with non-neoplastic gastric tissue. LBH589 inhibited proliferation of cancer cells in vitro. LBH589 down-regulated expression of genes that mediate anthracycline resistance by activating expression of Cbp/p300-interacting transactivator, with Glu/Asp-rich carboxy-terminal domain 2 (CITED2), a gene that mediates sensitivity to chemotherapeutics. Pre-incubation of cells with an HDAC inhibitor and overexpression of CITED2-sensitized gastric cell lines to anthracycline-mediated cell death. In CEA/Tag mice, LBH589 induced tumor-cell expression of CITED2 and increased the efficacy of anthracycline to reduce tumor growth. Levels of CITED2 were increased in gastric tumor samples from patients who had complete responses to epirubicin. CONCLUSIONS: The HDAC inhibitor LBH589 can overcome the resistance of mouse gastric cancer cells to anthracyclines by inducing expression of CITED2. Levels of CITED2 in gastric tumors correlate with patients' response to epirubicin. LBH589 might be used to increase the response of patients to anthracyclines.

The Ras inhibitors caveolin-1 and docking protein 1 activate peroxisome proliferator-activated receptor γ through spatial relocalization at helix 7 of its ligand-binding domain.

Peroxisome proliferator-activated receptor γ (PPARγ) is a transcription factor that promotes differentiation and cell survival in the stomach. PPARγ upregulates and interacts with caveolin-1 (Cav1), a scaffold protein of Ras/mitogen-activated protein kinases (MAPKs). The cytoplasmic-to-nuclear localization of PPARγ is altered in gastric cancer (GC) patients, suggesting a so-far-unknown role for Cav1 in spatial regulation of PPARγ signaling. We show here that loss of Cav1 accelerated proliferation of normal stomach and GC cells in vitro and in vivo. Downregulation of Cav1 increased Ras/MAPK-dependent phosphorylation of serine 84 in PPARγ and enhanced nuclear translocation and ligand-independent transcription of PPARγ target genes. In contrast, Cav1 overexpression sequestered PPARγ in the cytosol through interaction of the Cav1 scaffolding domain (CSD) with a conserved hydrophobic motif in helix 7 of PPARγ's ligand-binding domain. Cav1 cooperated with the endogenous Ras/MAPK inhibitor docking protein 1 (Dok1) to promote the ligand-dependent transcriptional activity of PPARγ and to inhibit cell proliferation. Ligand-activated PPARγ also reduced tumor growth and upregulated the Ras/MAPK inhibitors Cav1 and Dok1 in a murine model of GC. These results suggest a novel mechanism of PPARγ regulation by which Ras/MAPK inhibitors act as scaffold proteins that sequester and sensitize PPARγ to ligands, limiting proliferation of gastric epithelial cells.