Glioblastoma is the most common form of primary brain tumor in adults and is essentially incurable. Despite aggressive treatment regimens centered on radiotherapy, tumor recurrence is inevitable and is thought to be driven by glioblastoma stem-like cells (GSC) that are highly radioresistant. DNA damage response pathways are key determinants of radiosensitivity but the extent to which these overlapping and parallel signaling components contribute to GSC radioresistance is unclear. Using a panel of primary patient-derived glioblastoma cell lines, we confirmed by clonogenic survival assays that GSCs were significantly more radioresistant than paired tumor bulk populations. DNA damage response targets ATM, ATR, CHK1, and PARP1 were upregulated in GSCs, and CHK1 was preferentially activated following irradiation. Consequently, GSCs exhibit rapid G 2 -M cell-cycle checkpoint activation and enhanced DNA repair. Inhibition of CHK1 or ATR successfully abrogated G 2 -M checkpoint function, leading to increased mitotic catastrophe and a modest increase in radiation sensitivity. Inhibition of ATM had dual effects on cell-cycle checkpoint regulation and DNA repair that were associated with greater radiosensitizing effects on GSCs than inhibition of CHK1, ATR, or PARP alone. Combined inhibition of PARP and ATR resulted in a profound radiosensitization of GSCs, which was of greater magnitude than in bulk populations and also exceeded the effect of ATM inhibition. These data demonstrate that multiple, parallel DNA damage signaling pathways contribute to GSC radioresistance and that combined inhibition of cell-cycle checkpoint and DNA repair targets provides the most effective means to overcome radioresistance of GSC. Cancer Res; 75(20); 4416-28. Ó2015 AACR.

Intrahepatic cholestasis of pregnancy (ICP) is a reversible pregnancy-specific cholestatic condition characterized by pruritus, elevated liver enzymes, and increased serum bile acids. It commences usually in the late second or third trimester, and quickly resolves after delivery. The incidence is higher in South American and Scandinavian countries (9.2%-15.6% and 1.5%, respectively) than in Europe (0.1%-0.2%). The etiology is multifactorial where genetic, endocrine, and environmental factors interact. Maternal outcome is usually benign, whereas fetal complications such as preterm labor, meconium staining, fetal distress, and sudden intrauterine fetal demise not infrequently lead to considerable perinatal morbidity and mortality. Ursodeoxycholic acid is shown to be the most efficient therapeutic agent with proven safety and efficacy. Management of ICP consists of careful monitoring of maternal hepatic function tests and serum bile acid levels in addition to the assessment of fetal well-being and timely delivery after completion of fetal pulmonary maturity. This review focuses on the current concepts about ICP based on recent literature data and presents an update regarding the diagnosis and management of this challenging issue.

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Objective:To evaluate the left venticular myocardial deformation parameters in normotensive obese children and adolescents by using 2-D speckle tracking echocardiography.Methods:This observational cross-sectional study included 69 children and adolescents (aged between 10-18), 38 were normotensive obese and 31 were normal weighted. All children underwent detailed two- dimentional, Doppler and two-dimentional speckle tracking echocardiography. Student t-test, Mann-Whitney U test, chi-square test and Pearson’s correlation were used in statistical analysis. Multiple linear regression analysis was used the determine independent variables on global longitudinal strain (GLS).Results:While in normal limits, diastolic blood pressure was significantly higher in obese group. Left ventricular end-diastolic diameter (LVDd) and end-systolic diameter (LVDs), interventricular septal thickness (IVSd), left ventricular posterior wall thickness (LPWD) and left ventricular mass index (LVM)/height2.7 were significantly higher in obese group compared to healthy peers (p=0.004, p=0.011, p<0.001, p=0.001, p<0.001) respectively. Obese subjects had reduced global longitudinal strain (GLS) values (p=0.001). Multiple linear regression analysis using the step-wise method were performed to assess the independent variables (age, body mass index, insulin resistance, systolic blood pressure, diastolic blood pressure, left ventricular diameters and LVM index (g/m2.7) affecting the dependent variable GLS. GLS was found significantly correlated with body mass index (BMI) (β:0.440, p:0.001; 95% CI: 0.104-0.311).Conclusion:Left ventricular strain parameters obtained by two dimentional speckle tracking echocardiography were diminished in obese children compared to normal subjects indicating that obesity in childhood is linked to decreased myocardial deformation even in the absence of comorbidities in early stages.

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