Medulloblastoma (MB) is the most common brain malignancy in children. Whole neural axis irradiation is the treatment of choice, but it often results in long-term neurocognitive and developmental impairment. Only insights into MB biology will lead to improved therapeutic outcome. Wingless (WNT) signalling deregulation occurs in up to 25% of sporadic tumors, but the specific role of nuclear beta-catenin and its involvement in the radioresponse remains unsettled. Therefore we studied the gamma-radiation response of two MB cell lines from cellular and molecular points of view. Our data show that the p53 wild-type cell line is more sensitive to ionizing radiations (IR) than the p53 mutated line, but apoptosis is also induced in p53-mutated cells, suggesting an alternative p53-independent mechanism. In addition, this study is the first to demonstrate that gamma-rays trigger the WNT system in our in vitro models. Further studies are required to test if this could explain the radiosensitivity of MB and the favorable prognostic value of nuclear beta-catenin in this tumor.

Medulloblastomas (MBs) associated with the Wnt activation represent a subgroup with a favorable prognosis, but it remains unclear whether Wnt activation confers a less aggressive phenotype and/or enhances radiosensitivity. To investigate this issue, we evaluated the biological behavior of an MB cell line, UW228-1, stably transfected with human β-catenin cDNA encoding a nondegradable form of β-catenin (UW-B) in standard culture conditions and after radiation treatment. We evaluated the expression, transcriptional activity, and localization of β-catenin in the stably transfected cells using immunofluorescence and WB. We performed morphological analysis using light and electron microscopy. We then analyzed changes in the invasiveness, growth, and mortality in standard culture conditions and after radiation. We demonstrated that (A) Wnt activation inhibited 97 % of the invasion capability of the cells, (B) the growth of the UW-B cells was statistically significantly lower than that of all the other control cells (p < 0.01), (C) the mortality of irradiated UW-B cells was statistically significantly higher than that of the controls and their nonirradiated counterparts (p < 0.05), and (D) morphological features of neuronal differentiation were observed in the Wnt-activated cells. In tissue samples, the Ki-67 labeling index (LI) was lower in β-catenin-positive samples compared to non-β-catenin positive ones. The Ki-67 LI median (LI = 40) of the nuclear β-catenin-positive tumor samples was lower than that of non-nuclear β-catenin-positive samples (LI = 50), but the difference was not statistically significant. Overall, our data suggest that activation of the Wnt pathway reduces the proliferation and invasion of MBs and increases the tumor's radiosensitivity.

Summary It is unknown whether moderate thrombocytopenia represents a risk factor for post‐partum haemorrhage (PPH). We assessed PPH risk among women with a platelet count of between 100 and 50 × 109/l and stratified the risk for O/non‐O blood group. We included consecutive women undergoing vaginal delivery or caesarean section with moderate thrombocytopenia. Women with >150 × 109/l platelets at delivery were selected as controls and matched for age, type of birth and ethnicity. Odds ratios (ORs) with their 95% confidence intervals (95% CIs) were calculated as risk estimates. A total of 94 thrombocytopenic women and 94 controls were included in the study. The rate of PPH was significantly higher in thrombocytopenic women than in controls (37% vs. 10%, p < 0.001); there was a higher risk of PPH in the thrombocytopenic group when compared to the control group (adjusted OR 4.7, 95% CI 2.1–10.8, p < 0.01) and this association was stronger in blood group O carriers (adjusted OR 11.0, 95% CI 2.4–49.6, p < 0.01). In conclusion, our study shows that a moderate thrombocytopenia is a risk factor for PPH, especially in blood group O carriers.

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Abstract. Lithium is the main therapeutic agent for the treatment of bipolar disorders but nerve cells are not the sole target of this drug. Indeed, lithium has been reported to target numerous cell types and to affect cell proliferation, differentiation and death. Lithium targets a variety of enzymes among which there is GSK-3ß and a number of cell responses elicited by lithium are mediated by the Wnt pathway that is involved in medulloblastoma (MB) pathogenesis. We studied the in vitro effects of lithium on two different MB cell lines: D283MED and DAOY. High doses of lithium inhibited GSK3-ß, decreased cell proliferation and induced nonapoptotic cell death in both cell lines independently by intracellular levels of ß-catenin that is consistently high only in D283MED. At clinical doses, the anti-neoplastic effects were observed only in this cell line, highlighting the importance of a specific molecular background in determining the target therapy response. In conclusion, lithium could be a promising drug in MB, but an accurate molecular profile predictive of drug response still needs to be clarified.