HP1-Mediated Formation of Alternative Lengthening of Telomeres-Associated PML Bodies Requires HIRA but Not ASF1a

Approximately 10% of cancers use recombination-mediated Alternative Lengthening of Telomeres (ALT) instead of telomerase to prevent telomere shortening. A characteristic of cells that utilize ALT is the presence of ALT-associated PML nuclear bodies (APBs) containing (TTAGGG)n DNA, telomere binding proteins, DNA recombination proteins, and heterochromatin protein 1 (HP1). The function of APBs is unknown and it is possible that they are functionally heterogeneous. Most ALT cells lack functional p53, and restoration of the p53/p21 pathway in these cells results in growth arrest/senescence and a substantial increase in the number of large APBs that is dependent on two HP1 isoforms, HP1α and HP1γ. Here we investigated the mechanism of HP1-mediated APB formation, and found that histone chaperones, HIRA and ASF1a, are present in APBs following activation of the p53/p21 pathway in ALT cells. HIRA and ASF1a were also found to colocalize inside PML bodies in normal fibroblasts approaching senescence, providing evidence for the existence of a senescence-associated ASF1a/HIRA complex inside PML bodies, consistent with a role for these proteins in induction of senescence in both normal and ALT cells. Moreover, knockdown of HIRA but not ASF1a significantly reduced p53-mediated induction of large APBs, with a concomitant reduction of large HP1 foci. We conclude that HIRA, in addition to its physical and functional association with ASF1a, plays a unique, ASF1a-independent role, which is required for the localization of HP1 to PML bodies and thus for APB formation

Small supratentorial, extraaxial primitive neuroectodermal tumor causing large intracerebral hematoma

A 16-year-old boy presented with an unusual case of a supratentorial, extraaxial small round blue cell tumor of the central nervous system, which was most likely a primitive neuroectodermal tumor (PNET). Preoperative computed tomography and magnetic resonance imaging showed a large multistage hematoma in the left central region. Intraoperatively, a small, superficial tumorous lesion was found between the sagittal sinus and a large cortical vein hidden by the hematoma. The histological diagnosis was PNET. This tumor is one of the most aggressive intracerebral tumors, not only in children, so treatment strategies must be early, profound, and interdisciplinary. This case represents an important example of atypical extraaxial appearance of this lesion, which should be considered in the differential diagnosis of cortical or subcortical hemorrhage, since complete resection of this lesion is critical for the successful treatment and outcome

A cooperative quay crane-based stochastic model to estimate vessel handling time

Having a good estimate of a vessel’s handling time is essential for planning and scheduling container terminal resources, such as berth positions, quay cranes (QCs) and transport vehicles. However, estimating the expected vessel handling time is not straightforward , because it depends on vessel characteristics, resource allocation decisions, and uncertainties in terminal processes. To estimate the expected vessel handling time, we propose a two-level stochastic model. The higher level model consists of a continuous-time Markov chain (CTMC) that captures the effect of QC assignment and scheduling on vessel handling time . The lower level model is a multi-class closed queuing network that models the dynamic interactions among the terminal resources and provides an estimate of the transition rate input parameters to the higher level CTMC model. We estimate the expected vessel handling times for several container load and unload profiles and discuss the effect of terminal layout parameters and crane service time variabilities on vessel handling times. From numerical experiments, we find that by having QCs cooperate, the vessel handling times are reduced by up to 15 %. The vessel handling time is strongly dependent on the variation in the QC service time and on the vehicle travel path topology