E-cadherin and α-, β- and γ-catenin expression in prostate cancers: correlation with tumour invasion

The E-cadherin–catenin complex plays an important role in establishing and maintaining intercellular connections and morphogenesis and reduced expression of its constituent molecules is associated with invasion and metastasis. In the present study, we examined E-cadherin and α-, β- and γ-catenin levels in tumour tissues obtained by radical prostatectomy in order to investigate the relationship with histopathological tumour invasion. Immunohistochemical findings for 45 prostate cancer specimens demonstrated aberrant expression of each molecule to be associated with dedifferentiation and, in addition, alteration of staining patterns for the three types of catenin was significantly correlated with capsular but not lymphatic or vascular invasion. The data thus suggest that three types of catenin may be useful predictive markers for biological aggressiveness of prostate cancer. © 1999 Cancer Research Campaig

A preliminary investigation to explore the cognitive resources of physicians experiencing difficulty in training

Background Treating patients is complex, and research shows that there are differences in cognitive resources between physicians who experience difficulties, and those who do not. It is possible that differences in some cognitive resources could explain the difficulties faced by some physicians. In this study, we explore differences in cognitive resources between different groups of physicians (that is, between native (UK) physicians and International Medical Graduates (IMG); those who continue with training versus those who were subsequently removed from the training programme); and also between physicians experiencing difficulties compared with the general population. Methods A secondary evaluation was conducted on an anonymised dataset provided by the East Midlands Professional Support Unit (PSU). One hundred and twenty one postgraduate trainee physicians took part in an Educational Psychology assessment through PSU. Referrals to the PSU were mainly on the basis of problems with exam progression and difficulties in communication skills, organisation and confidence. Cognitive resources were assessed using the Wechsler Adult Intelligence Scale (WAIS-IV). Physicians were categorised into three PSU outcomes: ‘Continued in training’, ‘Removed from training’ and ‘Active’ (currently accessing the PSU). Results Using a one-sample Z test, we compared the referred physician sample to a UK general population sample on the WAIS-IV and found the referred sample significantly higher in Verbal Comprehension (VCI; z = 8.78) and significantly lower in Working Memory (WMI; z = −4.59). In addition, the native sample were significantly higher in Verbal Comprehension than the UK general population sample (VCI; native physicians: z = 9.95, p < .001, d = 1.25), whilst there was a lesser effect for the difference between the IMG sample and the UK general population (z = 2.13, p = .03, d = 0.29). Findings also showed a significant difference in VCI scores between those physicians who were ‘Removed from training’ and those who ‘Continued in training’. Conclusions Our results suggest it is important to understand the cognitive resources of physicians to provide a more focussed explanation of those who experience difficulties in training. This will help to implement more targeted interventions to help physicians develop compensatory strategies

Modulation of the β-Catenin Signaling Pathway by the Dishevelled-Associated Protein Hipk1

BACKGROUND:Wnts are evolutionarily conserved ligands that signal through beta-catenin-dependent and beta-catenin-independent pathways to regulate cell fate, proliferation, polarity, and movements during vertebrate development. Dishevelled (Dsh/Dvl) is a multi-domain scaffold protein required for virtually all known Wnt signaling activities, raising interest in the identification and functions of Dsh-associated proteins. METHODOLOGY:We conducted a yeast-2-hybrid screen using an N-terminal fragment of Dsh, resulting in isolation of the Xenopus laevis ortholog of Hipk1. Interaction between the Dsh and Hipk1 proteins was confirmed by co-immunoprecipitation assays and mass spectrometry, and further experiments suggest that Hipk1 also complexes with the transcription factor Tcf3. Supporting a nuclear function during X. laevis development, Myc-tagged Hipk1 localizes primarily to the nucleus in animal cap explants, and the endogenous transcript is strongly expressed during gastrula and neurula stages. Experimental manipulations of Hipk1 levels indicate that Hipk1 can repress Wnt/beta-catenin target gene activation, as demonstrated by beta-catenin reporter assays in human embryonic kidney cells and by indicators of dorsal specification in X. laevis embryos at the late blastula stage. In addition, a subset of Wnt-responsive genes subsequently requires Hipk1 for activation in the involuting mesoderm during gastrulation. Moreover, either over-expression or knock-down of Hipk1 leads to perturbed convergent extension cell movements involved in both gastrulation and neural tube closure. CONCLUSIONS:These results suggest that Hipk1 contributes in a complex fashion to Dsh-dependent signaling activities during early vertebrate development. This includes regulating the transcription of Wnt/beta-catenin target genes in the nucleus, possibly in both repressive and activating ways under changing developmental contexts. This regulation is required to modulate gene expression and cell movements that are essential for gastrulation

Telomerase modulates Wnt signalling by association with target gene chromatin

Stem cells are controlled, in part, by genetic pathways frequently dysregulated during human tumorigenesis. Either stimulation of Wnt/β-catenin signalling or overexpression of telomerase is sufficient to activate quiescent epidermal stem cells in vivo, although the mechanisms by which telomerase exerts these effects are not understood. Here we show that telomerase directly modulates Wnt/β-catenin signalling by serving as a cofactor in a β-catenin transcriptional complex. The telomerase protein component TERT (telomerase reverse transcriptase) interacts with BRG1 (also called SMARCA4), a SWI/SNF-related chromatin remodelling protein, and activates Wnt-dependent reporters in cultured cells and in vivo. TERT serves an essential role in formation of the anterior–posterior axis in Xenopus laevis embryos, and this defect in Wnt signalling manifests as homeotic transformations in the vertebrae of Tert(−/−) mice. Chromatin immunoprecipitation of the endogenous TERT protein from mouse gastrointestinal tract shows that TERT physically occupies gene promoters of Wnt-dependent genes. These data reveal an unanticipated role for telomerase as a transcriptional modulator of the Wnt/ β-catenin signalling pathway