Simulation and Optimization of ESA Designs for Space Plasma Missions

A novel electrostatic analyzer (ESA) simulation method that differs significantly from traditional methods is presented in this study, the "reverse-fly" simulation method. The simulation process and its applications are discussed in detail. This method is tested by comparing its results to the published test data of three experimental instruments; The Proton Electrostatic Analyzer-High Geometric Factor (PESA-H) instrument on the Wind mission [Lin, et al. 1995], the 2π-Toroidal Analyzer (2πTA) of Young, et al., [1988], and the Hot Plasma Composition Analyzer (HPCA) to be used in the upcoming Magnetospheric Multi-scale (MMS) mission. The strong agreement between simulation and experimental results verifies the accuracy of this technique. Our results reveal detailed properties of ESA response that are not practical to assess using laboratory data. This simulation method then is used to compare the transmission characteristics of five published ESA geometries to efficiently determine the optimal ESA geometry for use in future space missions. We show that the simulation methods described here are an important contribution to instrument design and development techniques and are critical to efficient and accurate verification of instrument performance

P08.36 Radioresistance of glioblastoma stem-like cells is associated with DNA replication stress, which is a promising therapeutic target

Introduction: The inevitability of tumour recurrence in glioblastoma (GBM) patients despite multi-modality treatment consisting of surgery, radiotherapy and chemotherapy, is reflected by a median survival of only 14 months. Tumour recurrence is thought to be driven by a small population of glioblastoma stem-like cells (GSCs) that are resistant to conventional therapies. DNA damage response (DDR) pathways have been shown to be up-regulated in GSCs and implicated in radioresistance and treatment failure. However the precise cause of enhanced DDR signalling in GSCs and the extent to which these signalling networks contribute to therapy resistance remains elusive. The objectives of this study were to investigate the underlying cause of DDR upregulation and treatment resistance in GSCs with a view to identifying novel and promising therapeutic targets. Materials and Methods: A panel of primary patient derived GBM cell lines cultured under conditions to enrich for or deplete the tumour stem cell population (GSC vs bulk respectively) were utilised in order to investigate enhanced GSC DDR under basal conditions and in response to ionising radiation. Confirmatory studies were also performed in cells sorted for the putative GSC marker CD133. The effects of a panel of small molecule DDR inhibitor agents on cell survival in GSC and bulk cells were quantified. Results: GSCs exhibited higher levels of total and activated DDR targets ATR, CHK1, ATM and PARP1 under basal conditions and were radioresistant compared to paired bulk populations. This was not due to increased levels of reactive oxygen species (ROS). Instead, we show that RPA is significantly higher in replicating GSCs and confirm by DNA fibre assays that GSCs and CD133+ cells have increased numbers of stalled replication forks, fewer new origins and slower DNA replication compared to bulk or CD133- populations, demonstrating for the first time that replication stress (RS) is a hallmark of GSCs. We identify increased expression of long neural genes as a likely mechanism for RS and DNA double strand breaks (DSBs) in GSCs and show that their radioresistance is reversed by dual inhibition of key RS and DDR proteins ATR and PARP. Conclusions: This study demonstrates the novel finding that replication stress is a hallmark of GSCs and resonates with recently published studies in neural progenitor cells showing that RS preferentially induces DNA DSB in long neural genes. Taken together, we implicate RS as a driver of enhanced DDR in GSCs and identify novel therapeutics with potential to improve clinical outcomes by overcoming the radioresistance of GB

The Herschel Exploitation of Local Galaxy Andromeda (HELGA). VI. The distribution and properties of molecular cloud associations in M31

In this paper we present a catalog of Giant Molecular Clouds (GMCs) in the An- dromeda (M31) galaxy extracted from the Herschel Exploitation of Local Galaxy An- dromeda (HELGA) dataset. GMCs are identified from the Herschel maps using a hierarchical source extraction algorithm. We present the results of this new catalog and characterise the spatial distribution and spectral energy properties of its clouds based on the radial dust/gas properties found by Smith et al (2012). 326 GMCs in the mass range 104 − 107 M⊙ are identified, their cumulative mass distribution is found to be proportional to M −2.34 in agreement with earlier studies. The GMCs appear to follow the same cloud mass to LCO correlation observed in the Milky Way. However, comparison between this catalog and interferometry studies also shows that the GMCs are substructured below the Herschel resolution limit suggesting that we are observing associations of GMCs. Following Gordon et al. (2006), we study the spatial structure of M31 by splitting the observed structure into a set of spiral arms and offset rings. We fit radii of 10.3 and 15.5 kpc to the two most prominent rings. We then fit a logarithmic spiral with a pitch angle of 8fdg9 to the GMCs not associated with either ring. Last, we comment on the effects of deprojection on our results and investigate the effect different models for M31's inclination will have on the projection of an unperturbed spiral arm system

Turbidity and Other Effects Resulting from Trafalgar Sandbank Dredging and Palmar Beach Nourishment

Beach-nourishment requirements on the southwestern Spanish coast have led to a significant increase in offshore dredging. Following a new research line, assessment of changes recorded in physicochemical and biological parameters due to dredging and dumping operations was performed at the Cape of Trafalgar and Palmar Beach during June and July 2008. Turbidity, salinity, pH, dissolved oxygen, temperature, and suspended-sediment data were collected at 10 stations. At the end of the study, a three-campaign monitoring program was implemented for 1 year to assess the possible effects on biological communities and sediment properties. The relevant results, such as the average extent of the sediment plume (< 400 m) and its persistence in the environment (< 10 min), are discussed in this paper. A precise correlation between turbidity and suspended sediments and the recovery time of ecological balance were also established. Furthermore, minimal and reversible effects caused by dredging and dumping operations in this type of marine environment were identified

The Herschel Exploitation of Local Galaxy Andromeda (HELGA) II: Dust and Gas in Andromeda

We present an analysis of the dust and gas in Andromeda, using Herschel images sampling the entire far-infrared peak. We fit a modified-blackbody model to ~4000 quasi-independent pixels with spatial resolution of ~140pc and find that a variable dust-emissivity index (beta) is required to fit the data. We find no significant long-wavelength excess above this model suggesting there is no cold dust component. We show that the gas-to-dust ratio varies radially, increasing from ~20 in the center to ~70 in the star-forming ring at 10kpc, consistent with the metallicity gradient. In the 10kpc ring the average beta is ~1.9, in good agreement with values determined for the Milky Way (MW). However, in contrast to the MW, we find significant radial variations in beta, which increases from 1.9 at 10kpc to ~2.5 at a radius of 3.1kpc and then decreases to 1.7 in the center. The dust temperature is fairly constant in the 10kpc ring (ranging from 17-20K), but increases strongly in the bulge to ~30K. Within 3.1kpc we find the dust temperature is highly correlated with the 3.6 micron flux, suggesting the general stellar population in the bulge is the dominant source of dust heating there. At larger radii, there is a weak correlation between the star formation rate and dust temperature. We find no evidence for 'dark gas' in M31 in contrast to recent results for the MW. Finally, we obtained an estimate of the CO X-factor by minimising the dispersion in the gas-to-dust ratio, obtaining a value of (1.9+/-0.4)x10^20 cm^-2 [K kms^-1]^-1.Comment: 19 pages, 18 figures. Submitted to ApJ April 2012; Accepted July 201

Transcriptional silencing of the Dickkopfs-3 (Dkk-3) gene by CpG hypermethylation in acute lymphoblastic leukaemia

Dkk-3 is a newly characterised mortalisation-related gene and an antagonist of the Wnt oncogenic signalling pathway whose expression is decreased in a variety of cancer cell lines, suggesting that the Dkk-3 gene, located at chromosome 11p15.1, functions as a tumour suppressor gene. Although 11p15 is a ‘hot spot’ for methylation in acute lymphoblastic leukaemia (ALL), the role of Dkk-3 abnormalities has never been evaluated in this disease. We analysed CpG island methylation of the Dkk-3 promoter in six ALL cell lines and 183 ALL patients. We observed Dkk-3 hypermethylation in all cell lines and in cells from 33% (60/183) of ALL patients. Moreover, Dkk-3 methylation was associated with decreased Dkk-3 mRNA expression and this expression was restored after exposure to the demethylating agent 5-AzaC. Clinical features did not differ between hypermethylated and unmethylated patients. Estimated disease-free survival (DFS) and overall survival at 10 and 11 years, respectively, were 49.8 and 45.6% for normal patients and 10.5 and 15.1% for hypermethylated patients (P¼0.001 and 0.09). Multivariate analysis demonstrated that Dkk-3 methylation was an independent prognostic factor predicting DFS (P¼0.0009). Our data suggest that Dkk-3 methylation occurs at an early stage in ALL pathogenesis and probably influences the clinical behaviour of the disease

HAGE (DDX43) is a biomarker for poor prognosis and a predictor of chemotherapy response in breast cancer

Background: HAGE protein is a known immunogenic cancer-specific antigen. Methods: The biological, prognostic and predictive values of HAGE expression was studied using immunohistochemistry in three cohorts of patients with BC (n=2147): early primary (EP-BC; n=1676); primary oestrogen receptor-negative (PER-BC; n=275) treated with adjuvant anthracycline-combination therapies (Adjuvant-ACT); and primary locally advanced disease (PLA-BC) who received neo-adjuvant anthracycline-combination therapies (Neo-adjuvant-ACT; n=196). The relationship between HAGE expression and the tumour-infiltrating lymphocytes (TILs) in matched prechemotherapy and postchemotherapy samples were investigated. Results: Eight percent of patients with EP-BC exhibited high HAGE expression (HAGEþ) and was associated with aggressive clinico-pathological features (Ps<0.01). Furthermore, HAGEþexpression was associated with poor prognosis in both univariate and multivariate analysis (Ps<0.001). Patients with HAGE+ did not benefit from hormonal therapy in high-risk ER-positive disease. HAGE+ and TILs were found to be independent predictors for pathological complete response to neoadjuvant-ACT; P<0.001. A statistically significant loss of HAGE expression following neoadjuvant-ACT was found (P=0.000001), and progression-free survival was worse in those patients who had HAGE+ residual disease (P=0.0003). Conclusions: This is the first report to show HAGE to be a potential prognostic marker and a predictor of response to ACT in patients with BC

Promoter hypermethylation of cancer-related genes: a strong independent prognostic factor in acute lymphoblastic leukemia

Promoter hypermethylation plays an important role in the inactivation of cancerrelated genes. This abnormality occurs early in leukemogenesis and seems to be associated with poor prognosis in acute lymphoblastic leukemia (ALL). To determine the extent of hypermethylation in ALL, we analyzed the methylation status of the CDH1, p73, p16, p15, p57, NES-1, DKK-3, CDH13, p14, TMS-1, APAF-1, DAPK, PARKIN, LATS-1, and PTEN genes in 251 consecutive ALL patients.Atotal of 77.3% of samples had at least 1 gene methylated, whereas 35.9% of cases had 4 or more genes methylated. Clinical features and complete remission rate did not differ among patients without methylated genes, patients with 1 to 3 methylated genes (methylated group A), or patients with more than 3 methylated genes (methylated group B). Estimated disease-free survival (DFS) and overall survival (OS) at 11 years were 75.5% and 66.1%, respectively, for the nonmethylated group; 37.2% and 45.5% for methylated group A; and 9.4% and 7.8% for methylated group B (P < .0001 and P .0004, respectively). Multivariate analysis demonstrated that the methylation profile was an independent prognostic factor in predicting DFS (P < .0001) and OS (P .003). Our results suggest that the methylation profile may be a potential new biomarker of risk prediction in AL