Personality traits predict perceived health-related quality of life in persons with multiple sclerosis.

BACKGROUND: Personality traits can affect health-related quality of life (HRQoL) in different disorders. In multiple sclerosis (MS), personality traits can determine patients' willingness to take on more risky treatment options, predispose to neuropsychiatric symptoms and affect coping strategies. OBJECTIVES: We investigated the role of personality traits as possible predictors of HRQoL in a large cohort of persons with MS (PwMS). METHODS: In total, 253 consecutively recruited PwMS were screened for intellectual deficits with Raven Colour Progressive Matrices (RCPM), state anxiety with STAI-X1 and major depression on a clinical basis. PwMS' self-perceived mental and physical health status was measured with the 36-Item Short Form Health Survey (SF-36), and the personality profile with the Eysenck Personality Questionnaire (EPQ-R). The correlation between HRQoL and personality traits was investigated by means of analysis of variance, adjusting for possible confounders. RESULTS: Of the 253 MS patients, 195 (F:M=2.75), aged 41.7±10.2 years were included in the analysis. The variance of SF-36 mental and physical composite score was largely explained by extraversion and neuroticism. CONCLUSIONS: Our data confirm that PwMS' HRQoL is largely influenced by personality traits, which may therefore act as predictors of perceived quality of life and should be included in clinical and experimental settings focusing on HRQoL.

A "twist box" code of p53 inactivation: twist box: p53 interaction promotes p53 degradation.

Twist proteins have been shown to contribute to cancer development and progression by impinging on different regulatory pathways, but their mechanism of action is poorly defined. By investigating the role of Twist in sarcomas, we found that Twist1 acts as a mechanism alternative to TP53 mutation and MDM2 overexpression to inactivate p53 in mesenchymal tumors. We provide evidence that Twist1 binds p53 C terminus through the Twist box. This interaction hinders key posttranslational modifications of p53 and facilitates its MDM2-mediated degradation. Our study suggests the existence of a Twist box code of p53 inactivation and provides the proof of principle that targeting the Twist box:p53 interaction might offer additional avenues for cancer treatment.

Regulation of cellular response to oncogenic and oxidative stress by Seladin-1.

Expression of multiple oncogenes and inactivation of tumour suppressors is required to transform primary mammalian cells into cancer cells. Activated Ha-RasV12 (Ras) is usually associated with cancer, but it also produces paradoxical premature senescence in primary cells by inducing reactive oxygen species followed by accumulation of tumour suppressors p53 and p16(INK4a) (ref. 4). Here we identify, using a direct genetic screen, Seladin-1 (also known as Dhcr24) as a key mediator of Ras-induced senescence. Following oncogenic and oxidative stress, Seladin-1 binds p53 amino terminus and displaces E3 ubiquitin ligase Mdm2 from p53, thus resulting in p53 accumulation. Additionally, Seladin-1 associates with Mdm2 independently of p53, potentially affecting other Mdm2 targets. Ablation of Seladin-1 causes the bypass of Ras-induced senescence in rodent and human fibroblasts, and allows Ras to transform these cells. Wild-type Seladin-1, but not mutants that disrupt its association with either p53 or Mdm2, suppresses the transformed phenotype. The same mutants are also inactive in directing p53-dependent oxidative stress response. These results show an unanticipated role for Seladin-1, previously implicated in Alzheimer's disease and cholesterol metabolism, in integrating cellular response to oncogenic and oxidative stress.

Alterations of beta-catenin pathway in non-melanoma skin tumors: loss of alpha-ABC nuclear reactivity correlates with the presence of beta-catenin gene mutation.

To determine the role of beta-catenin pathway in human skin carcinogenesis, 135 non-melanoma skin tumors were analyzed for beta-catenin expression and gene mutations. Intense nucleo-cytoplasmic immunoreactivity for C terminus beta-catenin antibodies was observed in all pilomatricomas and in single cases of trichoepithelioma and squamous cell carcinoma showing peculiar signs of matrical differentiation. Moderate increase of beta-catenin nuclear staining was detected in a significant proportion of basal cell carcinomas, Bowen disease, spiroadenomas, and occasionally also in squamous cell carcinomas, but in these neoplasms only a limited fraction of tumor cells accumulated beta-catenin. Molecular analysis revealed that beta-catenin gene mutations are a peculiar feature of skin tumors with matrical differentiation and correlate with a pattern of intense and diffuse beta-catenin nuclear expression. In contrast, adenomatous polyposis coli (APC) and AXIN2 mutations were not involved in skin tumorigenesis. Analysis of Wnt pathway revealed that TCF-1 and MITF-M were selectively induced in the tumor types harboring beta-catenin mutations, indicating that a Wnt/beta-catenin pathway involving TCF-1 and MITF-M is activated in these tumors. Interestingly, high expression levels of TCF-3 were found in basal cell carcinomas and spiroadenomas. TCF-3 is reported to act as a negative modulator of beta-catenin degradation pathway. Thus, the moderate increase of beta-catenin nuclear staining detected in these tumor types might, at least in part, be due to a TCF-3-dependent mechanism. Finally, we found that the presence of beta-catenin mutations significantly correlated with loss of nuclear immunoreactivity for an antibody raised against the N terminus of beta-catenin (alphaABC). Thus, a combined analysis with C terminus-beta-catenin antibodies and alphaABC Ab may represent a powerful investigative approach for the detection of beta-catenin structural alterations.