Crosstalk between kinases, phosphatases and miRNAs in cancer.

Reversible phosphorylation of proteins, performed by kinases and phosphatases, is the major post translational protein modification in eukaryotic cells. This intracellular event represents a critical regulatory mechanism of several signaling pathways and can be related to a vast array of diseases, including cancer. Cancer research has produced increasing evidence that kinase and phosphatase activity can be compromised by mutations and also by miRNA silencing, performed by small non-coding and endogenously produced RNA molecules that lead to translational repression. miRNAs are believed to target about one-third of human mRNAs while a single miRNA may target about 200 transcripts simultaneously. Regulation of the phosphorylation balance by miRNAs has been a topic of intense research over the last years, spanning topics going as far as cancer aggressiveness and chemotherapy resistance. By addressing recent studies that have shown miRNA expression patterns as phenotypic signatures of cancers and how miRNA influence cellular processes such as apoptosis, cell cycle control, angiogenesis, inflammation and DNA repair, we discuss how kinases, phosphatases and miRNAs cooperatively act in cancer biology.

Glucocorticoids in vivo induce both insulin hypersecretion and enhanced glucose sensitivity of stimulus-secretion coupling in isolated rat islets.

Although glucocorticoids are widely used as antiinflammatory agents in clinical therapies, they may cause serious side effects that include insulin resistance and hyperinsulinemia. To study the potential functional adaptations of the islet of Langerhans to in vivo glucocorticoid treatment, adult Wistar rats received dexamethasone (DEX) for 5 consecutive days, whereas controls (CTL) received only saline. The analysis of insulin release in freshly isolated islets showed an enhanced secretion in response to glucose in DEX-treated rats. The study of Ca(2+) signals by fluorescence microscopy also demonstrated a higher response to glucose in islets from DEX-treated animals. However, no differences in Ca(2+) signals were found between both groups with tolbutamide or KCl, indicating that the alterations were probably related to metabolism. Thus, mitochondrial function was explored by monitoring oxidation of nicotinamide dinucleotide phosphate autofluorescence and mitochondrial membrane potential. Both parameters revealed a higher response to glucose in islets from DEX-treated rats. The mRNA and protein content of glucose transporter-2, glucokinase, and pyruvate kinase was similar in both groups, indicating that changes in these proteins were probably not involved in the increased mitochondrial function. Additionally, we explored the status of Ca(2+)-dependent signaling kinases. Unlike calmodulin kinase II, we found an augmented phosphorylation level of protein kinase C alpha as well as an increased response of the phospholipase C/inositol 1,4,5-triphosphate pathway in DEX-treated rats. Finally, an increased number of docked secretory granules were observed in the beta-cells of DEX animals using transmission electron microscopy. Thus, these results demonstrate that islets from glucocorticoid-treated rats develop several adaptations that lead to an enhanced stimulus-secretion coupling and secretory capacity.

[Breast-conserving surgery and irradiation for early breast cancer: value of surgical clips in the surgical cavity]. / Association radiochirurgicale conservatrice des cancers du sein de petit volume: intérêt des clips chirurgicaux dans le lit de tumorectomie.

PURPOSE: To evaluate, qualitatively and quantitatively, the role of surgical clips in planning the tumor bed electron or brachytherapy boost in patients undergoing breast-conserving surgery and radiotherapy. PATIENTS AND METHODS: In 60 patients with breast cancer stage I or II, the excision cavity boundaries were marked by clips at surgery. Patients received a boost with brachytherapy (n = 51) or electron beam (n = 9) after whole breast irradiation. The boost target volume was first planned using clinical, mammography and operative information and its accuracy evaluated by screening the surgical clips and, if necessary, adjusting the field to encompass all clips and to include the scar. Dosimetry was retrospectively performed for each brachytherapy patient and for each surgical clip. RESULTS: It was necessary to modify the target volume field in 11 cases (18%). The average dose received by the surgical clips was 116.1% of the dose delivered to the reference isodose (median: 101.75%, range: 16-457%). However, dose heterogeneity was important in the same patient and between patients. CONCLUSION: Delineation of the boost target volume with surgical clips is more accurate than with clinical landmarks alone but this technique does not allow measurements of the clip-chest wall and clip-skin distances. Virtual simulation with CT-scan cuts is recommended for optimising boost planning.