IGFBP-3 inhibits Wnt signaling in metastatic melanoma cells.

In previous works, we have shown that insulin-like growth factor-binding protein-3 (IGFBP-3), a tissue and circulating protein able to bind to IGFs, decreases drastically in the blood serum of patients with diffuse metastatic melanoma. In agreement with the clinical data, recombinant IGFBP-3 was found to inhibit the motility and invasiveness of cultured metastatic melanoma cells and to prevent growth of grafted melanomas in mice. The present work was aimed at identifying the signal transduction pathways underlying the anti-tumoral effects of IGFBP-3. We show that the anti-tumoral effect of IGFBP-3 is due to inhibition of the Wnt pathway and depends upon the presence of CD44, a receptor protein known to modulate Wnt signaling. Once it has entered the cell, IGFBP-3 binds the Wnt signalosome interacting specifically with its component GSK-3β. As a consequence, the β-catenin destruction complex dissociates from the LRP6 Wnt receptor and GSK-3β is activated through dephosphorylation, becoming free to target cytoplasmic β-catenin which is degraded by the proteasomal pathway. Altogether, the results suggest that IGFBP-3 is a novel and effective inhibitor of Wnt signaling. As IGFBP-3 is a physiological protein which has no detectable toxic effects either on cultured cells or live mice, it might qualify as an interesting new therapeutic agent in melanoma, and potentially many other cancers with a hyperactive Wnt signaling

Multiple dimensions of semantic and perceptual similarity contribute to mnemonic discrimination for pictures

People often misrecognize objects that are similar to those they have previously encountered. These mnemonic discrimination errors are attributed to shared memory representations (gist) typically characterized in terms of meaning. In two experiments, we investigated multiple semantic and perceptual relations that may contribute: at the concept level, a feature-based measure of concept confusability quantified each concept’s tendency to activate other similar concepts via shared features; at the item level, rated item exemplarity indexed the degree to which the specific depicted objects activated their particular concepts. We also measured visual confusability over items using a computational model of vision, and an index of color confusability. Participants studied single (Experiment 1, N = 60) or multiple (Experiment 2, N = 60) objects for each basic-level concept, followed by a recognition memory test including studied items, similar lures, and novel items. People were less likely to recognize studied items with high concept confusability, and less likely to falsely recognize their lures. This points to weaker basic-level semantic gist representations for objects with more confusable concepts because of greater emphasis on coarse processing of shared features relative to fine-grained processing of individual concepts. In contrast, people were more likely to misrecognize lures that were better exemplars of their concept, suggesting that enhanced basic-level semantic gist processing increased errors due to gist across items. False recognition was also more frequent for more visually confusable lures. The results implicate semantic similarity at multiple levels and highlight the importance of perceptual as well as semantic relations

THE USE OF MICRO NEAR-INFRARED SPECTROSCOPY AND PRINCIPAL COMPONENT ANALYSIS (PCA) TO DETERMINE ORIGIN AND SOURCE OF WOOD PELLET

Qualitative properties of woody biofuel need to be declared due to their great influence on the combustion process. The furnace performance and the environmental impact could be improved with major monitoring of the physical and chemical characteristics of incoming biofuel. Furthermore, raw components origin should be tracked in the whole supply chain, promoting traceability. The lack of a unique characterization system could be overtaken with the Near Infrared (NIR) spectroscopy application as a cheaper, faster, and no-invasive tool to investigate main wood components and origin discrimination based on spectral differences. So, a portable NIRScan Nano has been applied to evaluate the separation between grounded softwood and hardwood but also a virgin and treated wood sample. Chemometric analysis of PCA has been carried out and the main results have been shown considering the score and loading plot of the pre-treated spectra. A rough separation between virgin and treated wood was obtained, mainly related to natural heterogeneity and the presence of discriminant chemical components. Similar results have been confirmed considering the variability between softwood and hardwood. According to the separation trends between each group, NIR proves to be an affordable and intuitive method to assess qualitative features of woody biofuel

CORRELATION BETWEEN INSULIN–LIKE GROWTH FACTOR BINDING PROTEIN-3 SERUM LEVEL AND MELANOMA PROGRESSION

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Phosphorilated ERK and eIF2alpha levels in melanoma cells.

The differentiation, proliferation and survival of melanocytes and melanoma cells are controlled at various levels. Recently, the importance of translational regulation in promoting and sustaining tumorigenesis is being increasingly recognized. The expression of certain translational factors transiently increases in normal cells in response to growth factors and is constitutively upregulated in tumor cells. The initiation factor IF2 is a central regulator of translation, and is the target of the main pathways of translational control. Activation of eIF2 kinases in response to stress or tumoral transformation has been reported; increased phosphorylation of eIF2 alpha has been correlated with a metastatic phenotype in some kinds of tumors. Phosphorylated ERK levels can be used as marker of cell growth since they are higher in the actively proliferating cells. We investigated whether phosphorylated eIF2-alpha and phosphorylated ERK levels are reliable markers of tumorigenic potential in different melanoma cell lines, and to get insight into the mechanisms whereby eIF2-alpha phosphorylation may modulate cellular transformation. In our melanoma cell lines, showed different levels of phosphorylated eIF2alpha and phosphorylated ERK, which were higher in the cell lines derived from metastatic tumours as compared to primary melanoma cell lines. We showed that after treatment with a MEK inhibitor, ERK phosphorylation was inhibited while eIF2alpha phosphorylation was enhanced in all melanoma cell lines. Moreover Western blotting and confocal analyses revealed that phosphorylated eIF2alpha was localized in the nucleus of melanoma cell lines, supporting a possible relationship between phosphorylation levels and subcellular localization of phosphorylated eIF2 alpha and cell proliferation in malignant melanoma

Metastatic volume: an old oncologic concept and a new prognostic factor for stage IV melanoma patients

BACKGROUND: The last melanoma staging system of the 2009 American Joint Committee on Cancer takes into account, for stage IV disease, the serum levels of lactate dehydrogenase (LDH) and the site of distant metastases. OBJECTIVE: Our aim was to compare the significance of metastatic volume, as evaluated at the time of stage IV melanoma diagnosis, with other clinical predictors of prognosis. METHODS: We conducted a retrospective multicentric study. To establish which variables were statistically correlated both with death and survival time, contingency tables were evaluated. The overall survival curves were compared using the Kaplan-Meier method. RESULTS: Metastatic volume and number of affected organs were statistically related to death. In detail, patients with a metastatic volume >15 cm(3) had a worse prognosis than those with a volume lower than this value (survival probability at 60 months: 6.8 vs. 40.9%, respectively). The Kaplan-Meier method confirmed that survival time was significantly related to the site(s) of metastases, to elevated LDH serum levels and to melanoma stage according to the latest system. CONCLUSION: Our results suggest that metastatic volume may be considered as a useful prognostic factor for survival among melanoma patients

Metastatic volume: An old oncologic concept and a new prognostic factor for stage IV melanoma patients

Background: The last melanoma staging system of the 2009 American Joint Committee on Cancer takes into account, for stage IV disease, the serum levels of lactate dehydrogenase (LDH) and the site of distant metastases. Objective: Our aim was to compare the significance of metastatic volume, as evaluated at the time of stage IV melanoma diagnosis, with other clinical predictors of prognosis. Methods: We conducted a retrospective multicentric study. To establish which variables were statistically correlated both with death and survival time, contingency tables were evaluated. The overall survival curves were compared using the Kaplan-Meier method. Results: Metastatic volume and number of affected organs were statistically related to death. In detail, patients with a metastatic volume >15 cm3 had a worse prognosis than those with a volume lower than this value (survival probability at 60 months: 6.8 vs. 40.9%, respectively). The Kaplan-Meier method confirmed that survival time was significantly related to the site(s) of metastases, to elevated LDH serum levels and to melanoma stage according to the latest system. Conclusion: Our results suggest that metastatic volume may be considered as a useful prognostic factor for survival among melanoma patients. © 2013 S. Karger AG, Basel