ATSAS is a comprehensive software suite for the analysis of small‐angle scattering data from dilute solutions of biological macromolecules or nanoparticles. It contains applications for primary data ...processing and assessment, ab initio bead modelling, and model validation, as well as methods for the analysis of flexibility and mixtures. In addition, approaches are supported that utilize information from X‐ray crystallography, nuclear magnetic resonance spectroscopy or atomistic homology modelling to construct hybrid models based on the scattering data. This article summarizes the progress made during the 2.5–2.8 ATSAS release series and highlights the latest developments. These include AMBIMETER, an assessment of the reconstruction ambiguity of experimental data; DATCLASS, a multiclass shape classification based on experimental data; SASRES, for estimating the resolution of ab initio model reconstructions; CHROMIXS, a convenient interface to analyse in‐line size exclusion chromatography data; SHANUM, to evaluate the useful angular range in measured data; SREFLEX, to refine available high‐resolution models using normal mode analysis; SUPALM for a rapid superposition of low‐ and high‐resolution models; and SASPy, the ATSAS plugin for interactive modelling in PyMOL. All these features and other improvements are included in the ATSAS release 2.8, freely available for academic users from https://www.embl‐hamburg.de/biosaxs/software.html.
Developments and improvements of the ATSAS software suite (versions 2.5–2.8) for analysis of small‐angle scattering data of biological macromolecules or nanoparticles are described.
We tested the hypotheses that the global incidence of bladder cancer was increasing but its mortality was reducing and its incidence was positively correlated with country-specific socioeconomic ...development. We retrieved data on age-standardized incidence and mortality rates/100,000 from the GLOBOCAN database in 2012. Temporal patterns were examined for 39 countries from the Cancer Incidence in Five Continents volumes I-X and other national registries. We evaluated the correlation between the incidence/mortality rates and Human Development Index (HDI)/ logarithmic values of Gross Domestic Product per capita (GDP). The average annual percent change of the incidence and mortality rates in the most recent 10 years was examined by joinpoint regression analysis. The highest incidence rates were observed in Southern Europe, Western Europe and North America. The mortality rates were the highest in Western Asia and Northern Africa. The incidence was positively correlated with HDI (r = 0.66 men; r = 0.50 women) and to a lesser extent logarithmic values of GDP per capita (r = 0.60 men; r = 0.50 women, all p < 0.01). Many European countries experienced incidence rise. A substantial mortality reduction was observed in most countries, yet increases in mortality rates were observed in the Philippines and Iceland. These findings identified countries where more preventive actions are required.
We examined the global incidence and mortality rates of liver cancer, and evaluated the association between incidence/mortality and socioeconomic development (Human Development Index HDI and Gross ...Domestic Product GDP) using linear regression analysis. The average annual percent change (AAPC) of the trends was evaluated from join-point regression analysis. The global incidence of liver cancer varied widely by nine-fold, and was negatively correlated with HDI (men: r = -0.232, p = 0.003; women: r = -0.369, p < 0.001) and GDP per capita (men: r = -0.164, p = 0.036; women: r = -0.212, p = 0.007). Its mortality showed a similarly negative correlation with both indices. The greatest incidence rise in men was observed in Poland (AAPC = 17.5, 95% C.I. = 5.6, 30.9) and Brazil (AAPC = 13.2, 95% C.I. = 5.9, 21.0), whereas Germany (AAPC = 6.6, 95% C.I = 2.0, 11.5) and Norway (AAPC = 6.5, 95% C.I. = 3.2, 10.0) had the greatest increase in women. The mortality rates paralleled the incidence rates in most countries. For mortality, Malta (AAPC = 11.5, 95% C.I. = 3.9, 19.8), Australia (AAPC = 6.8, 95% C.I. = 2.2, 11.5) and Norway (APCC = 5.6, 95% C.I. = 2.8, 8.5) reported the biggest increase among men; whilst Australia (AAPC = 13.4, 95% C.I. = 7.8, 19.4) and Singapore (AAPC = 7.7, 95% C.I. = 4.1, 11.5) showed the most prominent rise among women. These epidemiological data identified countries with potentially increasing trends of liver cancer for preventive actions.
Non-small cell lung cancer (NSCLC) is a prevalent and devastating disease that claims more lives than breast, prostate, colon and pancreatic cancers combined. Current research suggests that standard ...chemotherapy regimens have been optimized to maximal efficiency. Promising new treatment strategies involve novel agents targeting molecular aberrations present in subsets of NSCLC. We evaluated 88 human NSCLC tumors of diverse histology and identified Mer and Axl as receptor tyrosine kinases (RTKs) overexpressed in 69% and 93%, respectively, of tumors relative to surrounding normal lung tissue. Mer and Axl were also frequently overexpressed and activated in NSCLC cell lines. Ligand-dependent Mer or Axl activation stimulated MAPK, AKT and FAK signaling pathways indicating roles for these RTKs in multiple oncogenic processes. In addition, we identified a novel pro-survival pathway-involving AKT, CREB, Bcl-xL, survivin, and Bcl-2-downstream of Mer, which is differentially modulated by Axl signaling. We demonstrated that short hairpin RNA (shRNA) knockdown of Mer or Axl significantly reduced NSCLC colony formation and growth of subcutaneous xenografts in nude mice. Mer or Axl knockdown also improved in vitro NSCLC sensitivity to chemotherapeutic agents by promoting apoptosis. When comparing the effects of Mer and Axl knockdown, Mer inhibition exhibited more complete blockade of tumor growth while Axl knockdown more robustly improved chemosensitivity. These results indicate that Mer and Axl have complementary and overlapping roles in NSCLC and suggest that treatment strategies targeting both RTKs may be more effective than singly-targeted agents. Our findings validate Mer and Axl as potential therapeutic targets in NSCLC and provide justification for development of novel therapeutic compounds that selectively inhibit Mer and/or Axl.
Abstract Background Prostate cancer (PCa) is a leading cause of mortality and morbidity globally, but its specific geographic patterns and temporal trends are under-researched. Objective To test the ...hypotheses that PCa incidence is higher and PCa mortality is lower in countries with higher socioeconomic development, and that temporal trends for PCa incidence have increased while mortality has decreased over time. Design, setting, and participants Data on age-standardized incidence and mortality rates in 2012 were retrieved from the GLOBOCAN database. Temporal patterns were assessed for 36 countries using data obtained from Cancer incidence in five continents volumes I–X and the World Health Organization mortality database. Correlations between incidence or mortality rates and socioeconomic indicators (human development index HDI and gross domestic product GDP) were evaluated. Outcome measurements and statistical analysis The average annual percent change in PCa incidence and mortality in the most recent 10 yr according to join-point regression. Results and limitations Reported PCa incidence rates varied more than 25-fold worldwide in 2012, with the highest incidence rates observed in Micronesia/Polynesia, the USA, and European countries. Mortality rates paralleled the incidence rates except for Africa, where PCa mortality rates were the highest. Countries with higher HDI ( r = 0.58) and per capita GDP ( r = 0.62) reported greater incidence rates. According to the most recent 10-yr temporal data available, most countries experienced increases in incidence, with sharp rises in incidence rates in Asia and Northern and Western Europe. A substantial reduction in mortality rates was reported in most countries, except in some Asian countries and Eastern Europe, where mortality increased. Data in regional registries could be underestimated. Conclusions PCa incidence has increased while PCa mortality has decreased in most countries. The reported incidence was higher in countries with higher socioeconomic development. Patient summary The incidence of prostate cancer has shown high variations geographically and over time, with smaller variations in mortality.
We tested the hypotheses that kidney cancer incidence was increasing globally whilst its mortality was reducing; and its incidence was positively correlated with country-specific socioeconomic ...development. The incidence and mortality figures of each country were projected to 2030. Data on age-standardized incidence/mortality rates were retrieved from the GLOBOCAN in 2012. Temporal patterns were examined for 39 countries from the Cancer Incidence in Five Continents volumes I-X and other national registries. We evaluated the correlation between the incidence/mortality rates and Human Development Index (HDI)/Gross Domestic Product (GDP). The average annual percent change of its incidence and mortality in the most recent 10 years was obtained from joinpoint regression. The highest incidence rates were observed in Eastern Europe and North America, while its mortality rates were the highest in European countries. Incidence was positively correlated with HDI and GDP per capita. Many countries experienced incidence rise over the most recent 10 years, and a substantial reduction in mortality rates was observed for a significant number of countries, yet increases in mortality rates were observed in Eastern Europe. By 2030, Brazil and Ecuador may have the greatest rise in incidence both in men and women, which requires urgent need for planning healthcare resources.
We performed a genome-wide association scan in 1461 patients with bipolar (BP) 1 disorder, 2008 controls drawn from the Systematic Treatment Enhancement Program for Bipolar Disorder and the ...University College London sample collections with successful genotyping for 372,193 single nucleotide polymorphisms (SNPs). Our strongest single SNP results are found in myosin5B (MYO5B; P=1.66 x 10(-7)) and tetraspanin-8 (TSPAN8; P=6.11 x 10(-7)). Haplotype analysis further supported single SNP results highlighting MYO5B, TSPAN8 and the epidermal growth factor receptor (MYO5B; P=2.04 x 10(-8), TSPAN8; P=7.57 x 10(-7) and EGFR; P=8.36 x 10(-8)). For replication, we genotyped 304 SNPs in family-based NIMH samples (n=409 trios) and University of Edinburgh case-control samples (n=365 cases, 351 controls) that did not provide independent replication after correction for multiple testing. A comparison of our strongest associations with the genome-wide scan of 1868 patients with BP disorder and 2938 controls who completed the scan as part of the Wellcome Trust Case-Control Consortium indicates concordant signals for SNPs within the voltage-dependent calcium channel, L-type, alpha 1C subunit (CACNA1C) gene. Given the heritability of BP disorder, the lack of agreement between studies emphasizes that susceptibility alleles are likely to be modest in effect size and require even larger samples for detection.
Oesophageal cancers (adenocarcinomas AC and squamous cell carcinomas SCC) are characterized by high incidence/mortality in many countries. We aimed to delineate its global incidence and mortality, ...and studied whether socioeconomic development and its incidence rate were correlated. The age-standardized rates (ASRs) of incidence and mortality of this medical condition in 2012 for 184 nations from the GLOBOCAN database; national databases capturing incidence rates, and the WHO mortality database were examined. Their correlations with two indicators of socioeconomic development were evaluated. Joinpoint regression analysis was used to generate trends. The ratio between the ASR of AC and SCC was strongly correlated with HDI (r = 0.535 men; r = 0.661 women) and GDP (r = 0.594 men; r = 0.550 women, both p < 0.001). Countries that reported the largest reduction in incidence in male included Poland (Average Annual Percent Change AAPC = -7.1, 95%C.I. = -12,-1.9) and Singapore (AAPC = -5.8, 95%C.I. = -9.5,-1.9), whereas for women the greatest decline was seen in Singapore (AAPC = -12.3, 95%C.I. = -17.3,-6.9) and China (AAPC = -5.6, 95%C.I. = -7.6,-3.4). The Philippines (AAPC = 4.3, 95%C.I. = 2,6.6) and Bulgaria (AAPC = 2.8, 95%C.I. = 0.5,5.1) had a significant mortality increase in men; whilst Columbia (AAPC = -6.1, 95%C.I. = -7.5,-4.6) and Slovenia (AAPC = -4.6, 95%C.I. = -7.9,-1.3) reported mortality decline in women. These findings inform individuals at increased risk for primary prevention.
To examine patterns of prescription opioid use before total joint replacement (TJR) and factors associated with continuous use of opioids before TJR.
We conducted an observational cohort study among ...Medicare enrollees aged ≥65 years who underwent TJR between 2010 and 2014. Preoperative opioid use was defined as having any opioid prescription in the 12-month period before TJR. Patients who had an opioid prescription every month for a 12-month period were defined as continuous users. We examined patients’ demographics, pain-related conditions, medication use, other comorbidities, healthcare utilization and their association with use of opioids before TJR.
A total of 473,781 patients underwent TJR:,155,516 THR and 318,265 TKR. Among the total cohort, 60.2% patients had any use of opioids and of those, 12.4% used opioids at least once a month continuously over the 12-month baseline period. Correlates of continuous opioid use included African American race (OR = 2.14, 95% confidence intervals (CI) = 2.01–2.28, compared to White patients), history of drug abuse (OR = 5.18, 95% CI = 3.95–6.79) and back pain (OR = 2.32, 95% CI = 2.24–2.39).
In this large cohort of patients undergoing TJR, over 60% ever used opioids and 12.4% of them continuously used opioids in the 12-month prior to surgery. Utilization of opioids became more frequent and high-dosed near the surgery. History of drug abuse, back pain, and African American race were strongly associated with continuous use of opioids preoperatively. Further research is needed to determine short-term and long-term risks of preoperative use of opioids in TJR patients and to optimize pre- and post-TJR pain management of patients with arthritis.
A 4‐year 9‐month‐old beagle was presented for a 2‐week history of acute onset of lowered tail carriage and faecal incontinence. Neurological examination was unremarkable except for an absent perineal ...reflex, there was no history of trauma. Blood work was unremarkable. Lumbosacral and coccygeal CT pre‐ and post‐intravenous contrast revealed a large sacrococcygeal disc extrusion with mineralised material extending from the level of S2 and to midbody of Cd1. A dorsal laminectomy was performed from the cranial margin of S2 to the caudal margin of Cd1. A large volume of mineralised disc material was removed. The material was confirmed on histopathology to be consistent with extruded nucleus pulposus. The patient regained faecal continence within 3 days of hospital discharge. Based on a literature search this is the first report of a sacrococcygeal disc extrusion resulting in faecal incontinence, with successful surgical management.
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