Colorectal cancer is a major cause of cancer death worldwide. A number of key oncogenes and tumor suppressor genes have been proposed to drive progression from healthy colonic epithelia to malignant ...tumors, including members of the Wnt/beta-catenin pathway. Recently, CpG island promoter hypermethylation was shown to cause inactivation of two extracellular Wnt inhibitors in colon cancer: secreted frizzled-related proteins (sFRPs) and Wnt inhibitory factor-1 (WIF-1). Here, we show for the first time that another extracellular Wnt inhibitor, the DICKKOPF-1 (DKK-1) gene, is transcriptionally silenced by CpG island promoter hypermethylation in colon cancer cell lines (n=9), whereas treatment with the DNA-demethylating agent 5-aza-2-deoxycytidine restored DKK-1 expression. Restoration of DKK-1 function in non-expressing cells bearing a truncated APC (Adenomatous Polyposis Coli) gene had no effect on beta-catenin/T-cell factor-dependent transcription, but induced tumor suppressor-like features such as reduced colony formation density and tumor growth inhibition in nude mice. These results suggest additional functions for DKK-1 other than inhibiting canonical Wnt signaling. In primary colorectal tumors, DKK-1 was found hypermethylated in 17% (nine of 54) of cases. Furthermore, while for both SFRP-1 and WIF-1 methylation-associated silencing occurred across the whole spectrum of colorectal tumorigenesis, DKK-1 promoter was selectively hypermethylated in advanced colorectal neoplasms (Duke's C and D tumors).
Abstract
In this paper, we describe the routine photometric calibration of data taken with the VISTA infrared camera (VIRCAM) instrument on the ESO Visible and Infrared Survey Telescope for Astronomy ...(VISTA) telescope. The broad-band ZYJHKs data are directly calibrated from Two Micron all Sky Survey (2MASS) point sources visible in every VISTA image. We present the empirical transformations between the 2MASS and VISTA, and Wide-Field Camera and VISTA, photometric systems for regions of low reddening. We investigate the long-term performance of VISTA+VIRCAM. An investigation of the dependence of the photometric calibration on interstellar reddening leads to these conclusions: (1) For all broad-band filters, a linear colour-dependent correction compensates the gross effects of reddening where E(B − V) < 5.0. (2) For Z and Y, there is a significantly larger scatter above E(B − V) = 5.0, and insufficient measurements to adequately constrain the relation beyond this value. (3) The JHKs filters can be corrected to a few per cent up to E(B − V) = 10.0. We analyse spatial systematics over month-long time-scales, both inter- and intradetector and show that these are present only at very low levels in VISTA. We monitor and remove residual detector-to-detector offsets. We compare the calibration of the main pipeline products: pawprints and tiles. We show how variable seeing and transparency affect the final calibration accuracy of VISTA tiles, and discuss a technique, grouting, for mitigating these effects. Comparison between repeated reference fields is used to demonstrate that the VISTA photometry is precise to better than ≃ 2 per cent for the YJHKs bands and 3 per cent for the Z bands. Finally, we present empirically determined offsets to transform VISTA magnitudes into a true Vega system.
Precision oncology research is challenging outside the contexts of oncogenic addiction and/or targeted therapies. We previously showed that phosphoproteomics is a powerful approach to reveal patient ...subsets of interest characterized by the activity of a few kinases where the underlying genomics is complex. Here, we conduct a phosphoproteomic screening of samples from HER2-negative female breast cancer receiving neoadjuvant paclitaxel (N = 130), aiming to find candidate biomarkers of paclitaxel sensitivity. Filtering 11 candidate biomarkers through 2 independent patient sets (N = 218) allowed the identification of a subgroup of patients characterized by high levels of CDK4 and filamin-A who had a 90% chance of achieving a pCR in response to paclitaxel. Mechanistically, CDK4 regulates filamin-A transcription, which in turn forms a complex with tubulin and CLIP-170, which elicits increased binding of paclitaxel to microtubules, microtubule acetylation and stabilization, and mitotic catastrophe. Thus, phosphoproteomics allows the identification of explainable factors for predicting response to paclitaxel.
Subsidence related to multiple natural and human-induced processes affects an increasing number of areas worldwide. Although this phenomenon may involve surface deformation with 3D displacement ...components, negative vertical movement, either progressive or episodic, tends to dominate. Over the last decades, differential SAR interferometry (DInSAR) has become a very useful remote sensing tool for accurately measuring the spatial and temporal evolution of surface displacements over broad areas. This work discusses the main advantages and limitations of addressing active subsidence phenomena by means of DInSAR techniques from an end-user point of view. Special attention is paid to the spatial and temporal resolution, the precision of the measurements, and the usefulness of the data. The presented analysis is focused on DInSAR results exploitation of various ground subsidence phenomena (groundwater withdrawal, soil compaction, mining subsidence, evaporite dissolution subsidence, and volcanic deformation) with different displacement patterns in a selection of subsidence areas in Spain. Finally, a cost comparative study is performed for the different techniques applied.
The practical efficacy of technologically promising metals for use in ultraviolet plasmonics (3–6 eV) is assessed by an exhaustive numerical analysis. This begins with estimates of the near- and ...far-field electromagnetic enhancement factors of isolated hemispherical and spherical metallic nanoparticles deposited on typical dielectric substrates like sapphire, from which the potential of each metal for plasmonic applications may be ascertained. The ultraviolet plasmonic behavior of aluminum, chromium, copper, gallium, indium, magnesium, palladium, platinum, rhodium, ruthenium, titanium, and tungsten was compared with the well-known behavior of gold and silver in the visible. After exploring this behavior for each metal as a function of nanoparticle shape and size, the deleterious effect caused by the metal’s native oxide is considered, and the potential for applications such as surface-enhanced Raman spectroscopy, accelerated photodegradation and photocatalysis is addressed.
The aim of this study was to investigate the possible role of STAT4 gene in the genetic predisposition to systemic sclerosis (SSc) susceptibility or clinical phenotype. A total of 1317 SSc patients ...896 with limited cutaneous SSc (lcSSc) and 421 with diffuse cutaneous SSc (dcSSc) and 3113 healthy controls, from an initial case–control set of Spanish Caucasian ancestry and five independent cohorts of European ancestry (The Netherlands, Germany, Sweden, Italy and USA), were included in the study. The rs7574865 polymorphism was selected as STAT4 genetic marker. We observed that the rs7574865 T allele was significantly associated with susceptibility to lcSSc in the Spanish population P = 1.9 × 10−5 odds ratio (OR) 1.61 95% confidence intervals (CI) 1.29–1.99, but not with dcSSc (P = 0.41 OR 0.84 95% CI 0.59–1.21). Additionally, a dosage effect was observed showing individuals with rs7574865 TT genotype higher risk for lcSSc (OR 3.34, P = 1.02 × 10−7 95% CI 2.11–5.31). The association of the rs7574865 T allele with lcSSc was confirmed in all the replication cohorts with different effect sizes (OR ranging between 1.15 and 1.86), as well as the lack of association of STAT4 with dcSSc. A meta-analysis to test the overall effect of the rs7574865 polymorphism showed a strong risk effect of the T allele for lcSSc susceptibility (pooled OR 1.54 95% CI 1.36–1.74; P < 0.0001). Our data show a strong and reproducible association of the STAT4 gene with the genetic predisposition to lcSSc suggesting that this gene seems to be one of the genetic markers influencing SSc phenotype.
The origin of the unification model for active galactic nuclei (AGN) was the detection of broad hydrogen recombination lines in the optical polarized spectrum of the Seyfert 2 galaxy (Sy2) NGC 1068. ...Since then, a search for the hidden broad-line region (HBLR) of nearby Sy2s started, but polarized broad lines have only been detected in ∼30–40 per cent of the nearby Sy2s observed to date. Here we present new VLT/FORS2 optical spectropolarimetry of a sample of 15 Sy2s, including Compton-thin and Compton-thick sources. The sample includes six galaxies without previously published spectropolarimetry, some of them normally treated as non-hidden BLR (NHBLR) objects in the literature, four classified as NHBLR, and five as HBLR based on previous data. We report ≥4σ detections of a HBLR in 11 of these galaxies (73 per cent of the sample) and a tentative detection in NGC 5793, which is Compton-thick according to the analysis of X-ray data performed here. Our results confirm that at least some NHBLRs are misclassified, bringing previous publications reporting differences between HBLR and NHBLR objects into question. We detect broad Hα and Hβ components in polarized light for 10 targets, and just broad Hα for NGC 5793 and NGC 6300, with line widths ranging between 2100 and 9600 km s−1. High bolometric luminosities and low column densities are associated with higher polarization degrees, but not necessarily with the detection of the scattered broad components.
Very few data exist on the management of adult patients diagnosed with primary immune thrombocytopenia (ITP). The objectives of this study were to describe the diagnostic and treatment patterns for ...ITP and to compare the findings to recent ITP guidelines. We retrospectively analyzed the medical records of adult ITP patients diagnosed with primary ITP between January 2011 and June 2012 and examined whether management strategies were consistent or not with eight recent guideline-recommended practices. Overall, median age at the diagnosis of the disease (
n
= 101) was 58 years and median platelet count 12 × 10
9
/L with 75.2 % of patients having symptoms of ITP. The study perceived two major shortcomings in the diagnostic approach: (1) failure to perform peripheral blood film examination in 22.8 % of patients, a test that is mandatory by all guidelines, and (2) ordinary bone marrow assessment in more than half of the patients at diagnosis (50.5 %), a test not routinely recommended by guidelines. Low appropriateness in therapeutic management of patients included (1) unjustified use of intravenous immunoglobulin in the absence of bleeding in 54.8 % of patients and (2) splenectomy not being deferred until 6–12 months from diagnosis (median 161 days). Data also reflect a trend towards the early use of thrombopoietin receptor agonists in the treatment of patients who are refractory to any first-line therapy. We have recognized important areas of inapropriateness in the diagnostic and therapeutic management of adult ITP patients. Compliance with established guidelines should be encouraged in order to improve patient outcomes.
Genetic events mediating transformation from premalignant monoclonal gammopathies (MG) to multiple myeloma (MM) are unknown. To obtain a comprehensive genomic profile of MG from the early to late ...stages, we performed high-resolution analysis of purified plasma cells from 20 MGUS, 20 smoldering MM (SMM) and 34 MM by high-density 6.0 SNP array. A progressive increase in the incidence of copy number abnormalities (CNA) from MGUS to SMM and to MM (median 5, 7.5 and 12 per case, respectively) was observed (P=0.006). Gains on 1q, 3p, 6p, 9p, 11q, 19p, 19q and 21q along with 1p, 16q and 22q deletions were significantly less frequent in MGUS than in MM. Although 11q and 21q gains together with 16q and 22q deletions were apparently exclusive of MM status, we observed that these abnormalities were also present in minor subclones in MGUS. Overall, a total of 65 copy number-neutral LOH (CNN-LOH) were detected. Their frequency was higher in active MM than in the asymptomatic entities (P=0.047). A strong association between genetic lesions and fragile sites was also detected. In summary, our study shows an increasing genomic complexity from MGUS to MM and identifies new chromosomal regions involved in CNA and CNN-LOH.
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