Thermal-stress analysis of a Fort St. Vrain core-support block under accident conditions

A thermoelastic stress analysis of a graphite core support block in the Fort St. Vrain High Temperature Gas Cooled Reactor is described. The support block is subjected to thermal stresses caused by a loss of forced circulation accident of the reactor system. Two- and three-dimensional finite element models of the core support block are analyzed using the ADINAT and ADINA codes, and results are given that verify the integrity of this structural component under the given accident condition

Systemic inflammatory response is a predictor of outcome in patients undergoing preoperative chemoradiation for locally advanced rectal cancer

Aim: Current management of locally advanced rectal cancer includes neoadjuvant chemoradiation in selected patients to increase the chance of a tumour-free circumferential resection margin. There is uncertainty over the role of and selection criteria for additional systemic therapy in this group of patients. In this retrospective study we investigate the association between markers of systemic inflammatory response (SIR) and outcome from treatment. Method: One hundred and fifteen patients with locally advanced rectal cancer undergoing preoperative chemoradiation had recording of full blood count parameters including neutrophil/lymphocyte ratio (NLR) and platelet/lymphocyte ratios (PLR). Postoperative surgical margins (R status) and pathological stage were documented. Outcome measures were overall survival (OS), time to local recurrence (TTLR) and disease-free survival (DFS). Cox regression analysis was performed to identify predictors of outcome. Results: Only NLR and R status were significant predictors for all outcome measures on univariate and multivariate analysis. Elevated NLR (≥ 5) was associated with decreased OS, [hazard ratio (HR) and 95% CI, 7.0 (2.6–19.2)], decreased TTLR [HR 3.8 (1.3–11.2)] and shorter DFS [HR 4.1 (1.7–9.8)]. Median survival for patients with an elevated NLR was 18.8 months compared with 54.4 months without an elevated NLR (P < 0.001). Conclusion: In addition to postoperative R-status, an elevated NLR is also a valuable prognostic marker in patients undergoing chemoradiation for locally advanced rectal carcinoma. It is associated with worse OS, TTLR and DFS. An elevated NLR may be a useful additional tool in guiding the decision-making process for adjuvant or neoadjuvant therapies

Phosphorylation of linker histones regulates ATP-dependent chromatin remodeling enzymes.

Item does not contain fulltextMembers of the ATP-dependent family of chromatin remodeling enzymes play key roles in the regulation of transcription, development, DNA repair and cell cycle control. We find that the remodeling activities of the ySWI/SNF, hSWI/SNF, xMi-2 and xACF complexes are nearly abolished by incorporation of linker histones into nucleosomal array substrates. Much of this inhibition is independent of linker histone-induced folding of the arrays. We also find that phosphorylation of the linker histone by Cdc2/Cyclin B kinase can rescue remodeling by ySWI/SNF. These results suggest that linker histones exert a global, genome-wide control over remodeling activities, implicating a new, obligatory coupling between linker histone kinases and ATP-dependent remodeling enzymes

Measuring the affordability of medicines: Importance and challenges

__Abstract__ The issue of affordability of health care services remains high on the (health) policy agenda. Determining whether health care services are affordable is complex, however, as the concept 'affordability' is inherently normative. With a focus on measuring affordability in low- and middle-income countries, we discuss different methods used to operationalize this concept. Using the example of medicine purchases in Indonesia, we show the choice of method and threshold to have a significant impact on outcomes. We argue it is important to fur

Inhibition of ATR opposes glioblastoma invasion through disruption of cytoskeletal networks and integrin internalisation via macropinocytosis

Background Glioblastomas have highly infiltrative growth patterns that contribute to recurrence and poor survival. Despite infiltration being a critical therapeutic target, no clinically useful therapies exist which counter glioblastoma invasion. Here, we report that inhibition of Ataxia telangiectasia and Rad 3 related kinase (ATR) reduces invasion of glioblastoma cells through dysregulation of cytoskeletal networks and subsequent integrin trafficking. Methods Glioblastoma motility and invasion were assessed in vitro and in vivo in response to ATR inhibition (ATRi) and ATR over-expression using timelapse microscopy, two orthotopic glioblastoma models and intravital imaging. Disruption to cytoskeleton networks and endocytic processing were investigated via high throughput, super resolution imaging and intravital imaging. Results High ATR expression was associated with significantly poorer survival in clinical datasets whilst histological, protein expression and spatial transcriptomics using glioblastoma tumour specimens revealed higher ATR expression at infiltrative margins. Pharmacological inhibition with two different compounds and RNAi targeting of ATR opposed invasion of glioblastoma, whereas overexpression of ATR drove migration. Subsequent investigation revealed that cytoskeletal dysregulation reduced macropinocytotic internalisation of integrins at growth cone-like structures, resulting in a tumour microtube retraction defect. The biological relevance and translational potential of these findings was confirmed using two orthotopic in vivo models of glioblastoma and intravital imaging. Conclusion We demonstrate a novel role for ATR in determining invasion in glioblastoma cells and propose that pharmacological targeting of ATR could have far reaching clinical benefits beyond radiosensitisation