[1] In this study, we present the collation and analysis of the gridded land-based dataset of indices of temperature and precipitation extremes: HadEX2. Indices were calculated based on station data using a consistent approach recommended by the World Meteorological Organization (WMO) Expert Team on Climate Change Detection and Indices, resulting in the production of 17 temperature and 12 precipitation indices derived from daily maximum and minimum temperature and precipitation observations. High-quality in situ observations from over 7000 temperature and 11,000 precipitation meteorological stations across the globe were obtained to calculate the indices over the period of record available for each station. Monthly and annual indices were then interpolated onto a 3.75 Â 2.5 longitude-latitude grid over the period 1901-2010. Linear trends in the gridded fields were computed and tested for statistical significance. Overall there was very good agreement with the previous HadEX dataset during the overlapping data period. Results showed widespread significant changes in temperature extremes consistent with warming, especially for those indices derived from daily minimum temperature over the whole 110 years of record but with stronger trends in more recent decades. Seasonal results showed significant warming in all seasons but more so in the colder months. Precipitation indices also showed widespread and significant trends, but the changes were much more spatially heterogeneous compared with temperature changes. However, results indicated more areas with significant increasing trends in extreme precipitation amounts, intensity, and frequency than areas with decreasing trends.Citation: Donat, M. G., et al. (2013), Updated analyses of temperature and precipitation extreme indices since the beginning of the twentieth century: The HadEX2 dataset,

We present the second update to a data set of gridded land‐based temperature and precipitation extremes indices: HadEX3. This consists of 17 temperature and 12 precipitation indices derived from daily, in situ observations and recommended by the World Meteorological Organization (WMO) Expert Team on Climate Change Detection and Indices (ETCCDI). These indices have been calculated at around 7,000 locations for temperature and 17,000 for precipitation. The annual (and monthly) indices have been interpolated on a 1.875°×1.25° longitude‐latitude grid, covering 1901–2018. We show changes in these indices by examining ”global”‐average time series in comparison with previous observational data sets and also estimating the uncertainty resulting from the nonuniform distribution of meteorological stations. Both the short and long time scale behavior of HadEX3 agrees well with existing products. Changes in the temperature indices are widespread and consistent with global‐scale warming. The extremes related to daily minimum temperatures are changing faster than the maximum. Spatial changes in the linear trends of precipitation indices over 1950–2018 are less spatially coherent than those for temperature indices. Globally, there are more heavy precipitation events that are also more intense and contribute a greater fraction to the total. Some of the indices use a reference period for calculating exceedance thresholds. We present a comparison between using 1961–1990 and 1981–2010. The differences between the time series of the temperature indices observed over longer time scales are shown to be the result of the interaction of the reference period with a warming climate. The gridded netCDF files and, where possible, underlying station indices are available from http://www.metoffice.gov.uk/hadobs/hadex3 and http://www.climdex.org.

Purpose: Gastric cancer is a curable disease if diagnosed at early stage. However, most cases are diagnosed at advanced stage because of the lack of screening programs. Therefore, the identification of plasma biomarkers for early detection is necessary. Experimental Design: To search for these biomarkers, we evaluated the DNA methylation patterns of 24 genes by Methylation-specific PCR in primary tissues from 32 retrospectively collected gastric cancer cases (testing group). Correlation between methylation and gene expression was evaluated in the MKN-45 cell line after treatment with 5-aza-2 ¶-deoxycytidine. The most frequently hypermethylated genes were next evaluated in primary tissues and plasma samples from 43 prospectively collected gastric cancer cases as well as plasma samples from 31 asymptomatic age-and gender-matched controls (validation group). Results: In the testing group, 11 genes were hypermethylated in at least 50% of cases (APC, SHP1, E-cadherin, ER, Reprimo, SEMA3B, 3OST2, p14, p15, DAPK , and p16). Eight genes (BRCA1, p73, RARb, hMLH1, RIZI, RUNX3, MGMT, and TIMP3) were statistically associated with a particular variant of gastric cancer, the signet-ring cell type (P = 0.03). Seven genes (APC, SHP1, E-cadherin, ER, Reprimo, SEMA3B, and 3OST2) were next evaluated in the validation group. We confirm the high frequency of methylation in primary tumors for all seven genes. However, only APC and Reprimo were frequently methylated in pair plasma samples. In asymptomatic controls, only Reprimo was infrequently methylated in comparison with plasma from gastric cancer cases (P < 0.001). Conclusion:Our results identified specific methylation profile associated to signet-ring cell-type histology and aberrant hypermethylation of Reprimo as a potential biomarker for early detection of gastric cancer.

BackgroundAngiogenesis, the process in which new blood vessels are formed from preexisting ones, is highly dependent on the presence of classical angiogenic factors. Recent evidence suggests that axonal guidance proteins and their receptors can also act as angiogenic regulators. Netrin, a family of laminin-like proteins, specifically Netrin-1 and 4, act via DCC/Neogenin-1 and UNC5 class of receptors to promote or inhibit angiogenesis, depending on the physiological context.MethodsMesenchymal stem cells secrete a broad set of classical angiogenic factors. However, little is known about the expression of non-canonical angiogenic factors such as Netrin-1. The aim was to characterize the possible secretion of Netrin ligands by Wharton’s jelly-derived mesenchymal stem cells (WJ-MSC). We evaluated if Netrin-1 presence in the conditioned media from these cells was capable of inducing angiogenesis both in vitro and in vivo, using human umbilical vein endothelial cells (HUVEC) and chicken chorioallantoic membrane (CAM), respectively. In addition, we investigated if the RhoA/ROCK pathway is responsible for the integration of Netrin signaling to control vessel formation.ResultsThe paracrine angiogenic effect of the WJ-MSC-conditioned media is mediated at least in part by Netrin-1 given that pharmacological blockage of Netrin-1 in WJ-MSC resulted in diminished angiogenesis on HUVEC. When HUVEC were stimulated with exogenous Netrin-1 assayed at physiological concentrations (10–200 ng/mL), endothelial vascular migration occurred in a concentration-dependent manner. In line with our determination of Netrin-1 present in WJ-MSC-conditioned media we were able to obtain endothelial tubule formation even in the pg/mL range. Through CAM assays we validated that WJ-MSC-secreted Netrin-1 promotes an increased angiogenesis in vivo. Netrin-1, secreted by WJ-MSC, might mediate its angiogenic effect through specific cell surface receptors on the endothelium, such as UNC5b and/or integrin α6β1, expressed in HUVEC. However, the angiogenic response of Netrin-1 seems not to be mediated through the RhoA/ROCK pathway.ConclusionsThus, here we show that stromal production of Netrin-1 is a critical component of the vascular regulatory machinery. This signaling event may have deep implications in the modulation of several processes related to a number of diseases where angiogenesis plays a key role in vascular homeostasis.Electronic supplementary materialThe online version of this article (doi:10.1186/s13287-017-0494-5) contains supplementary material, which is available to authorized users.

BackgroundThe role of demographic factors, climatic conditions, school cycles, and connectivity patterns in shaping the spatio-temporal dynamics of pandemic influenza is not clearly understood. Here we analyzed the spatial, age and temporal evolution of the 2009 A/H1N1 influenza pandemic in Chile, a southern hemisphere country covering a long and narrow strip comprising latitudes 17°S to 56°S.MethodsWe analyzed the dissemination patterns of the 2009 A/H1N1 pandemic across 15 regions of Chile based on daily hospitalizations for severe acute respiratory disease and laboratory confirmed A/H1N1 influenza infection from 01-May to 31-December, 2009. We explored the association between timing of pandemic onset and peak pandemic activity and several geographical and demographic indicators, school vacations, climatic factors, and international passengers. We also estimated the reproduction number (R) based on the growth rate of the exponential pandemic phase by date of symptoms onset, estimated using maximum likelihood methods.ResultsWhile earlier pandemic onset was associated with larger population size, there was no association with connectivity, demographic, school or climatic factors. In contrast, there was a latitudinal gradient in peak pandemic timing, representing a 16-39-day lag in disease activity from the southern regions relative to the northernmost region (P < 0.001). Geographical differences in latitude of Chilean regions, maximum temperature and specific humidity explained 68.5% of the variability in peak timing (P = 0.01). In addition, there was a decreasing gradient in reproduction number from south to north Chile (P < 0.0001). The regional mean R estimates were 1.6-2.0, 1.3-1.5, and 1.2-1.3 for southern, central and northern regions, respectively, which were not affected by the winter vacation period.ConclusionsThere was a lag in the period of most intense 2009 pandemic influenza activity following a South to North traveling pattern across regions of Chile, significantly associated with geographical differences in minimum temperature and specific humidity. The latitudinal gradient in timing of pandemic activity was accompanied by a gradient in reproduction number (P < 0.0001). Intensified surveillance strategies in colder and drier southern regions could lead to earlier detection of pandemic influenza viruses and improved control outcomes.