Independent prognostic value of fascin immunoreactivity in stage III–IV colonic adenocarcinoma

Fascin, an actin-bundling protein involved in cell motility, has been shown to be upregulated in several types of carcinomas. In this study, we investigated the expression of fascin in 228 advanced colonic adenocarcinoma patients with a long follow-up. Fascin expression was compared with several clinicopathologic parameters and survival. Overall, fascin immunoreactivity was detected in 162 (71%) tumours with a prevalence for right-sided tumours (P<0.001). Fascin correlated significantly with sex, tumour grade and stage, mucinous differentiation, number of metastatic lymph nodes, extranodal tumour extension, and the occurrence of distant metastases. Patients with fascin-expressing tumours experienced a shorter disease-free and overall survival in comparison with those with negative tumours, and fascin immunoreactivity emerged as an independent prognostic factor in the multivariate analysis. Moreover, patients with the same tumour stages could be stratified in different risk categories for relapse and progression according to fascin expression. Our findings suggest that fascin is a useful prognostic marker for colonic adenocarcinomas

E2F1-Mediated Upregulation of p19INK4d Determines Its Periodic Expression during Cell Cycle and Regulates Cellular Proliferation

BACKGROUND: A central aspect of development and disease is the control of cell proliferation through regulation of the mitotic cycle. Cell cycle progression and directionality requires an appropriate balance of positive and negative regulators whose expression must fluctuate in a coordinated manner. p19INK4d, a member of the INK4 family of CDK inhibitors, has a unique feature that distinguishes it from the remaining INK4 and makes it a likely candidate for contributing to the directionality of the cell cycle. p19INK4d mRNA and protein levels accumulate periodically during the cell cycle under normal conditions, a feature reminiscent of cyclins. METHODOLOGY/PRINCIPAL FINDINGS: In this paper, we demonstrate that p19INK4d is transcriptionally regulated by E2F1 through two response elements present in the p19INK4d promoter. Ablation of this regulation reduced p19 levels and restricted its expression during the cell cycle, reflecting the contribution of a transcriptional effect of E2F1 on p19 periodicity. The induction of p19INK4d is delayed during the cell cycle compared to that of cyclin E, temporally separating the induction of these proliferative and antiproliferative target genes. Specific inhibition of the E2F1-p19INK4d pathway using triplex-forming oligonucleotides that block E2F1 binding on p19 promoter, stimulated cell proliferation and increased the fraction of cells in S phase. CONCLUSIONS/SIGNIFICANCE: The results described here support a model of normal cell cycle progression in which, following phosphorylation of pRb, free E2F induces cyclin E, among other target genes. Once cyclinE/CDK2 takes over as the cell cycle driving kinase activity, the induction of p19 mediated by E2F1 leads to inhibition of the CDK4,6-containing complexes, bringing the G1 phase to an end. This regulatory mechanism constitutes a new negative feedback loop that terminates the G1 phase proliferative signal, contributing to the proper coordination of the cell cycle and provides an additional mechanism to limit E2F activity

UBE3A reinstatement as a disease-modifying therapy for Angelman syndrome

Half a century ago, Harry Angelman reported three patients with overlapping clinical features, now well known as Angelman syndrome. Angelman syndrome is caused by mutations affecting the maternally inherited UBE3A gene, which encodes an E3-ubiquitin ligase that is critical for typical postnatal brain development. Emerging evidence indicates that UBE3A plays a particularly important role in the nucleus. However, the critical substrates that are controlled by UBE3A remain elusive, which hinders the search for effective treatments. Moreover, given the multitude of signalling mechanisms that are derailed, it is unlikely that targeting a single pathway is going to be very effective. Therefore, expectations are very high for approaches that aim to restore UBE3A protein levels. A particular promising strategy is an antisense oligonucleotide approach, which activates the silenced paternal UBE3A gene. When successful, such treatments potentially offer a disease-modifying therapy for Angelman syndrome and several other neurodevelopmental disorders

A global compilation of diatom silica oxygen isotope records from lake sediment

Oxygen isotopes in biogenic silica (δ18O BSi) from lake sediments allow for quantitative reconstruction of past hydroclimate and proxy–model comparison in terrestrial environments. The signals of individual records have been attributed to different factors, such as air temperature (T air ), atmospheric circulation patterns, hydrological changes and lake evaporation. Here, we provide 55 composite down–core records published to date and complemented with additional lake basin parameters (e.g. lake water residence time and catchment size) to best characterize the signal properties. Records feature widely different temporal coverage and resolution ranging from decadal–scale records covering the last 150 years to records with multi–millennial scale resolution spanning glacial–interglacial cycles. Best coverage in number of records (N=37) and datapoints (N=2112) is available for northern hemispheric (NH) extra–tropic regions throughout the Holocene (corresponding to Marine Isotope Stage 1; MIS 1)

A global compilation of diatom silica oxygen isotope records from lake sediment: additional information on the lakes and sites corresponding to the records

Oxygen isotopes in biogenic silica (δ18O BSi) from lake sediments allow for quantitative reconstruction of past hydroclimate and proxy–model comparison in terrestrial environments. The signals of individual records have been attributed to different factors, such as air temperature (T air ), atmospheric circulation patterns, hydrological changes and lake evaporation. Here, we provide 55 composite down–core records published to date and complemented with additional lake basin parameters (e.g. lake water residence time and catchment size) to best characterize the signal properties. Records feature widely different temporal coverage and resolution ranging from decadal–scale records covering the last 150 years to records with multi–millennial scale resolution spanning glacial–interglacial cycles. Best coverage in number of records (N=37) and datapoints (N=2112) is available for northern hemispheric (NH) extra–tropic regions throughout the Holocene (corresponding to Marine Isotope Stage 1; MIS 1)

A global compilation of diatom silica oxygen isotope records from lake sediment: individual datasets in a single table

Oxygen isotopes in biogenic silica (δ18O BSi) from lake sediments allow for quantitative reconstruction of past hydroclimate and proxy–model comparison in terrestrial environments. The signals of individual records have been attributed to different factors, such as air temperature (T air ), atmospheric circulation patterns, hydrological changes and lake evaporation. Here, we provide 55 composite down–core records published to date and complemented with additional lake basin parameters (e.g. lake water residence time and catchment size) to best characterize the signal properties. Records feature widely different temporal coverage and resolution ranging from decadal–scale records covering the last 150 years to records with multi–millennial scale resolution spanning glacial–interglacial cycles. Best coverage in number of records (N=37) and datapoints (N=2112) is available for northern hemispheric (NH) extra–tropic regions throughout the Holocene (corresponding to Marine Isotope Stage 1; MIS 1)