The prognostic significance of low-frequency somatic mutations in metastatic cutaneous melanoma

Background: Little is known about the prognostic significance of somatically mutated genes in metastatic melanoma (MM). We have employed a combined clinical and bioinformatics approach on tumor samples from cutaneous melanoma (SKCM) as part of The Cancer Genome Atlas project (TCGA) to identify mutated genes with potential clinical relevance. Methods: After limiting our DNA sequencing analysis to MM samples (n = 356) and to the CANCER CENSUS gene list, we filtered out mutations with low functional significance (snpEFF). We performed Cox analysis on 53 genes that were mutated in ≥3% of samples, and had ≥50% difference in incidence of mutations in deceased subjects versus alive subjects. Results: Four genes were potentially prognostic [RAC1, FGFR1, CARD11, CIITA; false discovery rate (FDR) 75% of the samples that exhibited corresponding DNA mutations. The low frequency, UV signature type and RNA expression of the 22 genes in MM samples were confirmed in a separate multi-institution validation cohort (n = 413). An underpowered analysis within a subset of this validation cohort with available patient follow-up (n = 224) showed that somatic mutations in SPEN and RAC1 reached borderline prognostic significance [log-rank favorable (p = 0.09) and adverse (p = 0.07), respectively]. Somatic mutations in SPEN, and to a lesser extent RAC1, were not associated with definite gene copy number or RNA expression alterations. High (>2+) nuclear plus cytoplasmic expression intensity for SPEN was associated with longer melanoma-specific overall survival (OS) compared to lower (≤ 2+) nuclear intensity (p = 0.048). We conclude that expressed somatic mutations in infrequently mutated genes beyond the well-characterized ones (e.g., BRAF, RAS, CDKN2A, PTEN, TP53), such as RAC1 and SPEN, may have prognostic significance in MM

Global, regional, and national age-sex-specific mortality and life expectancy, 1950–2017: a systematic analysis for the Global Burden of Disease Study 2017

BACKGROUND: Assessments of age-specific mortality and life expectancy have been done by the UN Population Division, Department of Economics and Social Affairs (UNPOP), the United States Census Bureau, WHO, and as part of previous iterations of the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD). Previous iterations of the GBD used population estimates from UNPOP, which were not derived in a way that was internally consistent with the estimates of the numbers of deaths in the GBD. The present iteration of the GBD, GBD 2017, improves on previous assessments and provides timely estimates of the mortality experience of populations globally. METHODS: The GBD uses all available data to produce estimates of mortality rates between 1950 and 2017 for 23 age groups, both sexes, and 918 locations, including 195 countries and territories and subnational locations for 16 countries. Data used include vital registration systems, sample registration systems, household surveys (complete birth histories, summary birth histories, sibling histories), censuses (summary birth histories, household deaths), and Demographic Surveillance Sites. In total, this analysis used 8259 data sources. Estimates of the probability of death between birth and the age of 5 years and between ages 15 and 60 years are generated and then input into a model life table system to produce complete life tables for all locations and years. Fatal discontinuities and mortality due to HIV/AIDS are analysed separately and then incorporated into the estimation. We analyse the relationship between age-specific mortality and development status using the Socio-demographic Index, a composite measure based on fertility under the age of 25 years, education, and income. There are four main methodological improvements in GBD 2017 compared with GBD 2016: 622 additional data sources have been incorporated; new estimates of population, generated by the GBD study, are used; statistical methods used in different components of the analysis have been further standardised and improved; and the analysis has been extended backwards in time by two decades to start in 1950. FINDINGS: Globally, 18·7% (95% uncertainty interval 18·4–19·0) of deaths were registered in 1950 and that proportion has been steadily increasing since, with 58·8% (58·2–59·3) of all deaths being registered in 2015. At the global level, between 1950 and 2017, life expectancy increased from 48·1 years (46·5–49·6) to 70·5 years (70·1–70·8) for men and from 52·9 years (51·7–54·0) to 75·6 years (75·3–75·9) for women. Despite this overall progress, there remains substantial variation in life expectancy at birth in 2017, which ranges from 49·1 years (46·5–51·7) for men in the Central African Republic to 87·6 years (86·9–88·1) among women in Singapore. The greatest progress across age groups was for children younger than 5 years; under-5 mortality dropped from 216·0 deaths (196·3–238·1) per 1000 livebirths in 1950 to 38·9 deaths (35·6–42·83) per 1000 livebirths in 2017, with huge reductions across countries. Nevertheless, there were still 5·4 million (5·2–5·6) deaths among children younger than 5 years in the world in 2017. Progress has been less pronounced and more variable for adults, especially for adult males, who had stagnant or increasing mortality rates in several countries. The gap between male and female life expectancy between 1950 and 2017, while relatively stable at the global level, shows distinctive patterns across super-regions and has consistently been the largest in central Europe, eastern Europe, and central Asia, and smallest in south Asia. Performance was also variable across countries and time in observed mortality rates compared with those expected on the basis of development. INTERPRETATION: This analysis of age-sex-specific mortality shows that there are remarkably complex patterns in population mortality across countries. The findings of this study highlight global successes, such as the large decline in under-5 mortality, which reflects significant local, national, and global commitment and investment over several decades. However, they also bring attention to mortality patterns that are a cause for concern, particularly among adult men and, to a lesser extent, women, whose mortality rates have stagnated in many countries over the time period of this study, and in some cases are increasing

The Information Content of the Yield Curve in Australia

This paper examines the expectation theory of the term structure of interest rates in Australia by looking at the information content of the yield curve. Cointegration results provide evidence that the slope coefficient of the yield curve is unity. Bivariate vector autoregressive analysis (VAR) indicates that the spread between the long term and the short term rates is informative about changes in the short rate. In addition, the spread between the short term rate and the official cash rate has predictive power for changes in the cash rate. These findings imply that the Reserve Bank of Australia could influence the long term rate by intervening on the official cash rate. Finally, the efficient market restrictions were tested and accepted by the data

Asymmetries in the European Monetary System: Evidence from Interest Rates

This paper tests for asymmetries in the European Monetary System (EMS). The analysis indicates that any asymmetric movements between German and other EMS interest rates originating from changes in the US rate are temporary and tend to be eliminated during subsequent periods through offsetting interest rate adjustments. Furthermore, the trivariate error correction vector autoregression analysis of interest rate relationships among the US, Germany and each of the other EMS countries suggests that German leadership is not an EMS-wide phenomenon, since it is confirmed only with respect to Belgium and France

Tests for efficiency in the forward eurodrachma market

Restrictions on short-term capital movements limit the openness of the Greek financial system. Non-overlapping data from the forward eurodrachma market are used to test the market-efficiency hypothesis. The combined use of unit-root and stationarity tests provide some evidence that the forward and the one-period ahead spot rates are cointegrated with a coefficient of unity, as required by the efficiency hypothesis. However, the cointegrating combination is serially correlated. This finding contradicts the market-efficiency hypothesis. © 1994, Taylor & Francis Group, LLC. All rights reserved

The Information Content of the Yield Curve in Australia

This paper examines the expectation theory of the term structure of interest rates in Australia by looking at the information content of the yield curve. Cointegration results provide evidence that the slope coefficient of the yield curve is unity. Bivariate vector autoregressive analysis (VAR) indicates that the spread between the long term and the short term rates is informative about changes in the short rate. In addition, the spread between the short term rate and the official cash rate has predictive power for changes in the cash rate. These findings imply that the Reserve Bank of Australia could influence the long term rate by intervening on the official cash rate. Finally, the efficient market restrictions were tested and accepted by the data.

Asymmetries in the European Monetary System: Evidence from Interest Ra tes

This paper tests for asymmetries in the European Monetary System (EMS). The analysis indicates that any asymmetric movements between German and other EMS interest rates originating from changes in the US rate are temporary and tend to be eliminated during subsequent periods through offsetting interest rate adjustments. Furthermore, the trivariate error correction vector autoregression analysis of interest rate relationships among the US, Germany and each of the other EMS countries suggests that German leadership is not an EMS-wide phenomenon, since it is confirmed only with respect to Belgium and France.