Endothelin receptor B antagonists decrease glioma cell viability independently of their cognate receptor

Background: Endothelin receptor antagonists inhibit the progression of many cancers, but research into their influence on glioma has been limited. Methods: We treated glioma cell lines, LN-229 and SW1088, and melanoma cell lines, A375 and WM35, with two endothelin receptor type B (ETRB)-specific antagonists, A-192621 and BQ788, and quantified viable cells by the capacity of their intracellular esterases to convert non-fluorescent calcein AM into green-fluorescent calcein. We assessed cell proliferation by labeling cells with carboxyfluorescein diacetate succinimidyl ester and quantifying the fluorescence by FACS analysis. We also examined the cell cycle status using BrdU/propidium iodide double staining and FACS analysis. We evaluated changes in gene expression by microarray analysis following treatment with A-192621 in glioma cells. We examined the role of ETRB by reducing its expression level using small interfering RNA (siRNA). Results: We report that two ETRB-specific antagonists, A-192621 and BQ788, reduce the number of viable cells in two glioma cell lines in a dose- and time-dependent manner. We describe similar results for two melanoma cell lines. The more potent of the two antagonists, A-192621, decreases the mean number of cell divisions at least in part by inducing a G2/M arrest and apoptosis. Microarray analysis of the effects of A-192621 treatment reveals up-regulation of several DNA damage-inducible genes. These results were confirmed by real-time RT-PCR. Importantly, reducing expression of ETRB with siRNAs does not abrogate the effects of either A-192621 or BQ788 in glioma or melanoma cells. Furthermore, BQ123, an endothelin receptor type A (ETRA)-specific antagonist, has no effect on cell viability in any of these cell lines, indicating that the ETRB-independent effects on cell viability exhibited by A-192621 and BQ788 are not a result of ETRA inhibition. Conclusion: While ETRB antagonists reduce the viability of glioma cells in vitro, it appears unlikely that this effect is mediated by ETRB inhibition or cross-reaction with ETRA. Instead, we present evidence that A-192621 affects glioma and melanoma viability by activating stress/DNA damage response pathways, which leads to cell cycle arrest and apoptosis. This is the first evidence linking ETRB antagonist treatment to enhanced expression of DNA damage-inducible genes

Who Watches the Watchmen? An Appraisal of Benchmarks for Multiple Sequence Alignment

Multiple sequence alignment (MSA) is a fundamental and ubiquitous technique in bioinformatics used to infer related residues among biological sequences. Thus alignment accuracy is crucial to a vast range of analyses, often in ways difficult to assess in those analyses. To compare the performance of different aligners and help detect systematic errors in alignments, a number of benchmarking strategies have been pursued. Here we present an overview of the main strategies--based on simulation, consistency, protein structure, and phylogeny--and discuss their different advantages and associated risks. We outline a set of desirable characteristics for effective benchmarking, and evaluate each strategy in light of them. We conclude that there is currently no universally applicable means of benchmarking MSA, and that developers and users of alignment tools should base their choice of benchmark depending on the context of application--with a keen awareness of the assumptions underlying each benchmarking strategy.Comment: Revie

High Energy Bounds on Soft N=4 SYM Amplitudes from AdS/CFT

Using the AdS/CFT correspondence, we study the high-energy behavior of colorless dipole elastic scattering amplitudes in N=4 SYM gauge theory through the Wilson loop correlator formalism and Euclidean to Minkowskian analytic continuation. The purely elastic behavior obtained at large impact-parameter L, through duality from disconnected AdS_5 minimal surfaces beyond the Gross-Ooguri transition point, is combined with unitarity and analyticity constraints in the central region. In this way we obtain an absolute bound on the high-energy behavior of the forward scattering amplitude due to the graviton interaction between minimal surfaces in the bulk. The dominant "Pomeron" intercept is bounded by alpha less than or equal to 11/7 using the AdS/CFT constraint of a weak gravitational field in the bulk. Assuming the elastic eikonal approximation in a larger impact-parameter range gives alpha between 4/3 and 11/7. The actual intercept becomes 4/3 if one assumes the elastic eikonal approximation within its maximally allowed range L larger than exp{Y/3}, where Y is the total rapidity. Subleading AdS/CFT contributions at large impact-parameter due to the other d=10 supergravity fields are obtained. A divergence in the real part of the tachyonic KK scalar is cured by analyticity but signals the need for a theoretical completion of the AdS/CFT scheme.Comment: 25 pages, 3 eps figure

Immunohistochemical evaluation of human epidermal growth factor receptor 2 and estrogen and progesterone receptors in breast carcinoma in Jordan

INTRODUCTION: Although breast carcinoma (BC) is the most common malignancy affecting Jordanian females and the affected population in Jordan is younger than that in the West, no information is available on its biological characteristics. Our aims in this study are to evaluate the expression of estrogen receptor (ER) and progesterone receptor (PR) and Her-2/neu overexpression in BC in Jordan, and to compare the expression of these with other prognostic parameters for BC such as histological type, histological grade, tumor size, patients' age, and number of lymph node metastases. METHOD: This is a retrospective study conducted in the Department of Pathology at Jordan University of Science and Technology. A confirmed 91 cases of BC diagnosed in the period 1995 to 1998 were reviewed and graded. We used immunohistochemistry to evaluate the expression of ER, PR, and Her-2. Immunohistochemical findings were correlated with age, tumor size, grade and axillary lymph node status. RESULTS: Her-2 was overexpressed in 24% of the cases. The mean age of Her-2 positive cases was 42 years as opposed to 53 years among Her-2 negative cases (p = 0.0001). Her-2 expression was inversely related to ER and PR expression. Her-2 positive tumors tended to be larger than Her-2 negative tumors with 35% overexpression among T3 tumors as opposed to 22% among T2 tumors (p = 0.13). Her-2 positive cases tended to have higher rates of axillary metastases, but this did not reach statistical significance. ER and PR positive cases were seen in older patients with smaller tumor sizes. CONCLUSION: Her-2 overexpression was seen in 24% of BC affecting Jordanian females. Her-2 overexpression was associated with young age at presentation, larger tumor size, and was inversely related to ER and PR expression. One-fifth of the carcinomas were Her-2 positive and ER negative. This group appears to represent an aggressive form of BC presenting at a young age with large primary tumors and a high rate of four or more axillary lymph node metastases

Asymptotic Energy Dependence of Hadronic Total Cross Sections from Lattice QCD

The nonperturbative approach to soft high-energy hadron-hadron scattering, based on the analytic continuation of Wilson-loop correlation functions from Euclidean to Minkowskian theory, allows to investigate the asymptotic energy dependence of hadron-hadron total cross sections in lattice QCD. In this paper we will show, using best fits of the lattice data with proper functional forms satisfying unitarity and other physical constraints, how indications emerge in favor of a universal asymptotic high-energy behavior of the kind B log^2 s for hadronic total cross sections.Comment: Revised and extended version; 29 pages, 4 figure

Changes in household food and drink purchases following restrictions on the advertisement of high fat, salt, and sugar products across the Transport for London network: A controlled interrupted time series analysis.

Funder: Cancer Research UKBACKGROUND: Restricting the advertisement of products with high fat, salt, and sugar (HFSS) content has been recommended as a policy tool to improve diet and tackle obesity, but the impact on HFSS purchasing is unknown. This study aimed to evaluate the impact of HFSS advertising restrictions, implemented across the London (UK) transport network in February 2019, on HFSS purchases. METHODS AND FINDINGS: Over 5 million take-home food and drink purchases were recorded by 1,970 households (London [intervention], n = 977; North of England [control], n = 993) randomly selected from the Kantar Fast Moving Consumer Goods panel. The intervention and control samples were similar in household characteristics but had small differences in main food shopper sex, socioeconomic position, and body mass index. Using a controlled interrupted time series design, we estimated average weekly household purchases of energy and nutrients from HFSS products in the post-intervention period (44 weeks) compared to a counterfactual constructed from the control and pre-intervention (36 weeks) series. Energy purchased from HFSS products was 6.7% (1,001.0 kcal, 95% CI 456.0 to 1,546.0) lower among intervention households compared to the counterfactual. Relative reductions in purchases of fat (57.9 g, 95% CI 22.1 to 93.7), saturated fat (26.4 g, 95% CI 12.4 to 40.4), and sugar (80.7 g, 95% CI 41.4 to 120.1) from HFSS products were also observed. Energy from chocolate and confectionery purchases was 19.4% (317.9 kcal, 95% CI 200.0 to 435.8) lower among intervention households than for the counterfactual, with corresponding relative reductions in fat (13.1 g, 95% CI 7.5 to 18.8), saturated fat (8.7 g, 95% CI 5.7 to 11.7), sugar (41.4 g, 95% CI 27.4 to 55.4), and salt (0.2 g, 95% CI 0.1 to 0.2) purchased from chocolate and confectionery. Relative reductions are in the context of secular increases in HFSS purchases in both the intervention and control areas, so the policy was associated with attenuated growth of HFSS purchases rather than absolute reduction in HFSS purchases. Study limitations include the lack of out-of-home purchases in our analyses and not being able to assess the sustainability of observed changes beyond 44 weeks. CONCLUSIONS: This study finds an association between the implementation of restrictions on outdoor HFSS advertising and relative reductions in energy, sugar, and fat purchased from HFSS products. These findings provide support for policies that restrict HFSS advertising as a tool to reduce purchases of HFSS products

Changes in household food and drink purchases following restrictions on the advertisement of high fat, salt, and sugar products across the Transport for London network: A controlled interrupted time series analysis.

Funder: Cancer Research UKBACKGROUND: Restricting the advertisement of products with high fat, salt, and sugar (HFSS) content has been recommended as a policy tool to improve diet and tackle obesity, but the impact on HFSS purchasing is unknown. This study aimed to evaluate the impact of HFSS advertising restrictions, implemented across the London (UK) transport network in February 2019, on HFSS purchases. METHODS AND FINDINGS: Over 5 million take-home food and drink purchases were recorded by 1,970 households (London [intervention], n = 977; North of England [control], n = 993) randomly selected from the Kantar Fast Moving Consumer Goods panel. The intervention and control samples were similar in household characteristics but had small differences in main food shopper sex, socioeconomic position, and body mass index. Using a controlled interrupted time series design, we estimated average weekly household purchases of energy and nutrients from HFSS products in the post-intervention period (44 weeks) compared to a counterfactual constructed from the control and pre-intervention (36 weeks) series. Energy purchased from HFSS products was 6.7% (1,001.0 kcal, 95% CI 456.0 to 1,546.0) lower among intervention households compared to the counterfactual. Relative reductions in purchases of fat (57.9 g, 95% CI 22.1 to 93.7), saturated fat (26.4 g, 95% CI 12.4 to 40.4), and sugar (80.7 g, 95% CI 41.4 to 120.1) from HFSS products were also observed. Energy from chocolate and confectionery purchases was 19.4% (317.9 kcal, 95% CI 200.0 to 435.8) lower among intervention households than for the counterfactual, with corresponding relative reductions in fat (13.1 g, 95% CI 7.5 to 18.8), saturated fat (8.7 g, 95% CI 5.7 to 11.7), sugar (41.4 g, 95% CI 27.4 to 55.4), and salt (0.2 g, 95% CI 0.1 to 0.2) purchased from chocolate and confectionery. Relative reductions are in the context of secular increases in HFSS purchases in both the intervention and control areas, so the policy was associated with attenuated growth of HFSS purchases rather than absolute reduction in HFSS purchases. Study limitations include the lack of out-of-home purchases in our analyses and not being able to assess the sustainability of observed changes beyond 44 weeks. CONCLUSIONS: This study finds an association between the implementation of restrictions on outdoor HFSS advertising and relative reductions in energy, sugar, and fat purchased from HFSS products. These findings provide support for policies that restrict HFSS advertising as a tool to reduce purchases of HFSS products

Efficacy and Safety of a New 20% Immunoglobulin Preparation for Subcutaneous Administration, IgPro20, in Patients With Primary Immunodeficiency

Subcutaneous human IgG (SCIG) therapy in primary immunodeficiency (PID) offers sustained IgG levels throughout the dosing cycle and fewer adverse events (AEs) compared to intravenous immunoglobulin (IVIG). A phase I study showed good local tolerability of IgPro20, a new 20% liquid SCIG stabilized with L-proline. A prospective, open-label, multicenter, single-arm, phase III study evaluated the efficacy and safety of IgPro20 in patients with PID over 15 months. Forty-nine patients (5–72 years) previously treated with IVIG received weekly subcutaneous infusions of IgPro20. The mean serum IgG level was 12.5 g/L. No serious bacterial infections were reported. There were 96 nonserious infections (rate 2.76/patient per year). The rate of days missed from work/school was 2.06/patient per year, and the rate of hospitalization was 0.2/patient per year. Ninety-nine percent of AEs were mild or moderate. No serious, IgPro20-related AEs were reported. IgPro20 effectively protected patients with PID against infections and maintained serum IgG levels without causing unexpected AEs