Prexasertib (LY2606368) reduces clonogenic survival by inducing apoptosis in primary patient-derived osteosarcoma cells and synergizes with cisplatin and talazoparib

Progress in the systemic control of osteosarcoma has been limited over the past decades thus indicating the urgent clinical need for the development of novel treatment strategies. Therefore, we have recently developed new preclinical models to study promising novel agents for the treatment of pediatric osteosarcoma. The checkpoint kinase (chk) inhibitor prexasertib (LY2606368) and its salt form (LSN2940930) have recently been shown to be active in adult and pediatric malignancies, including sarcoma. We have now tested the potency of prexasertib in clonogenic survival assays in two new lines of primary patient-derived osteosarcoma cells and in two established osteosarcoma cell lines as a single agent and in combination with cisplatin and the poly ADP-ribose polymerase (PARP) inhibitor talazoparib. Prexasertib alone results in strongly reduced clonogenic survival at low nanomolar concentrations and acts by affecting cell cycle progression, induction of apoptosis and induction of double-stranded DNA breakage at concentrations that are well below clinically tolerable and safe plasma concentrations. In combination with cisplatin and talazoparib, prexasertib acts in a synergistic fashion. Chk1 inhibition by prexasertib and its combination with the DNA damaging agent cisplatin and the PARP-inhibitor talazoparib thus emerges as a potential new treatment option for pediatric osteosarcoma which will now have to be tested in preclinical primary patient derived in vivo models and clinical studies.     

Accuracy assessment of three‐dimensional surface reconstructions of teeth from Cone Beam Computed Tomography scans

Summary The use of three‐dimensional (3D) models of the dentition obtained from cone beam computed tomography (CBCT) is becoming increasingly more popular in dentistry. A recent trend is to replace the traditional dental casts with digital CBCT models for diagnosis, treatment planning and simulation. The accuracy of these models was previously assessed through comparing linear physical and radiographical measurements. However, this assessment technique is both observer and landmark dependent. The accuracy of 3D CBCT teeth reconstructions is yet to be reliably measured. To assess the accuracy of 3D CBCT reconstructions of the teeth using a semi‐automated and observer‐independent method and to assess the influence of field of view (FoV) selection on reconstruction accuracy. Fully dentate upper and lower dry human jaws, placed in a plastic box and immersed in water, were scanned using CBCT with small, medium and large FoV. The teeth were then scanned separately using MicroCT. Cone beam computed tomography and MicroCT 3D teeth models were compared, and mean surface difference was calculated per tooth for each FoV. Mean and (maximum) differences between MicroCT and CBCT were 120 ± 40 (max. 679) μm, 157 ± 39 (max. 824) μ and 207 ± 80 (max. 862) μm for the small, medium and large FoV, respectively. Cone beam computed tomography models were larger than MicroCT because of larger voxel size. Our results indicate that CBCT may provide accurate 3D reconstructions of the teeth that can be useful for some clinical applications.     

Parents and preschool workers’ perceptions of competence,collaboration, and strategies for addressing bullying in early childhood

The purpose of this study was to explore and compare parents’ (n?=?141) and preschool workers’ (n?=?81) perceptions of bullying with respect to preschool workers’ competence, collaboration with parents, and strategies for dealing with bullying. Whereas most participants held positive views about their collaboration, preschool workers tended to be more critical of parents than vice versa. With respect to strategies, we found that the order of preferred approaches was largely consistent across groups, yet the two groups differed in the degree to which they supported certain approaches. Among parents, lower perceptions of children’s well-being and increased exposure to bullying were associated with more negative views of collaboration and preschool competence. Parents who had little direct exposure to bullying were more likely to report that they lacked the knowledge needed to evaluate the competence of preschool workers. Taken together with previous research, these findings suggest that preschools often rely on a reactive approach to including parents in the process of addressing bullying. We argue that a more proactive stance is warranted.     

Length polymorphism of heterochromatic segment of the Y chromosome in boys with acute leukemia

The extent of length polymorphisms of the heterochromatic and euchromatic segment of the human Y chromosome were investigated in 15 boys with acute leukemia and were compared with 15 normal controls. A greater value of the Yh/F index in relation to controls was established (P < 0.05). The length of the euchromatic segment was also shorter in the patients than the controls (P < 0.05).     

Effects on Plasma Glucose Concentration of Light-for-date Infants and Infants of Diabetic Mothers of Feeds Supplemented with a Glucose Polymer

ABSTRACT. Serial plasma glucose estimations were performed in 44 light-for-date infants and 17 infants of diabetic mothers fed 2, 3 or 4-hourly with feeds containing 10 % additional carbohydrate in the form of a glucose polymer (Caloreen). In the infants fed 2 and 3-hourly, plasma glucose was higher following the high carbohydrate feeds, particularly immediately before the next feed was due. Given 4-hourly, the high carbohydrate feed had little effect in most light-for-date infants, and in one light-for-date infant and two infants of diabetic mothers the plasma glucose was lower at the end of 4 hours than following normal formula. It is concluded that the addition of glucose polymer to feeds given 2 and 3 hourly has a potentially useful effect in neonates at risk of developing hypoglycaemia, but it cannot be used to increase the feed interval to 4 hours.     

Pharyngeal diverticula

A series of 73 hypopharyngeal (Zenker's) diverticula is reported and the choice of treatment and technique of excision are discussed. The problems of excision include operation on an infected site with limited access but few patients are unfit for the procedure. Preoperatively the sac should be packed and the oesophagus stented. The side of approach is unimportant as the condition is essentially midline. Cricopharyngeal myotomy appears to reduce the recurrence rate, possibly by improving coordination of pharyngeal contraction and upper oesophageal relaxation. The use of electrocoagulation is not recommended as 20% of patients require repeated general anaesthesia and the procedure fails in 13%. For all but the smallest pouches, excision is the treatment of choice.