Evasion of immune surveillance and suppression of the immune system are important hallmarks of tumour development in colon cancer. The goal of this study was to establish a tumour profile based on ...biomarkers that reflect a tumour's immune susceptibility status and to determine their relation to patient outcome.
The study population consisted of 285 stage I-IV colon cancer patients of which a tissue micro array (TMA) was available. Sections were immunohistochemically stained for the presence of Foxp3+ cells and tumour expression of HLA Class I (HLA-A, -B, -C) and non-classical HLA-E and HLA-G. All markers were combined for further analyses, resulting in three tumour immune phenotypes: strong immune system tumour recognition, intermediate immune system tumour recognition and poor immune system tumour recognition.
Loss of HLA class I expression was significantly related to a better OS (P-value 0.005) and DFS (P-value 0.008). Patients with tumours who showed neither HLA class I nor HLA-E or -G expression (phenotype a) had a significant better OS and DFS (P-value <0.001 and 0.001, respectively) compared with phenotype b (OS HR: 4.7, 95% CI: 1.2-19.0, P=0.001) or c (OS HR: 8.2, 95% CI: 2.0-34.2, P=0.0001). Further, the tumour immune phenotype was an independent predictor for OS and DFS (P-value 0.009 and 0.013, respectively).
Tumours showing absence of HLA class I, HLA-E and HLA-G expressions were related to a better OS and DFS. By combining the expression status of several immune-related biomarkers, three tumour immune phenotypes were created that related to patient outcome. These immune phenotypes represented significant, independent, clinical prognostic profiles in colon cancer.
Tumour aggressiveness might be related to the degree of main cancer hallmark acquirement of tumour cells, reflected by expression levels of specific biomarkers. We investigated the expression of ...Aldh1, Survivin, and EpCAM, together reflecting main cancer hallmarks, in relation to clinical outcome of colorectal cancer (CRC) patients.
Immunohistochemistry was performed using a tumour tissue microarray of TNM (Tumour, Node, Metastasis)-stage I-IV CRC tissues. Single-marker expression or their combination was assessed for associations with the clinical outcome of CRC patients (N=309).
Increased expression of Aldh1 or Survivin, or decreased expression of EpCAM was each associated with poor clinical outcome, and was therefore identified as clinically unfavourable expression. Analyses of the combination of all three markers showed worse clinical outcome, specifically in colon cancer patients, with an increasing number of markers showing unfavourable expression. Hazard ratios ranged up to 8.3 for overall survival (P<0.001), 36.6 for disease-specific survival (P<0.001), and 27.1 for distant recurrence-free survival (P<0.001).
Our data identified combined expression levels of Aldh1, Survivin, and EpCAM as strong independent prognostic factors, with high hazard ratios, for survival and tumour recurrence in colon cancer patients, and therefore reflect tumour aggressiveness.
We present the results of analysis of "snapshot" spectra of 253 metal-poor halo stars-3.8 , Fe/H , -1.5 obtained in the HERES survey. The snapshot spectra have been obtained with VLT/UVES and have ...typically S/N 6 54 per pixel (ranging from 17 to 308), R 6 20 000, l = 3760-4980 AA. This sample represents the major part of the complete HERES sample of 373 stars; however, the CH strong content of the sample is not dealt with here. The spectra are analysed using an automated line profile analysis method based on the Spectroscopy Made Easy (SME) codes of Valenti & Piskunov. Elemental abundances of moderate precision (absolute rms errors of order 0.25 dex, relative rms errors of order 0.15 dex) have been obtained for 22 elements, C, Mg, Al, Ca, Sc, Ti, V, Cr, Mn, Fe, Co, Ni, Zn, Sr, Y, Zr, Ba, La, Ce, Nd, Sm, and Eu, where detectable. Of these elements, 14 are usually detectable at the 3s confidence level for our typical spectra. The remainder can be detected in the least metal-poor stars of the sample, spectra with higher than average S/N, or when the abundance is enhanced. Among the sample of 253 stars, disregarding four previously known comparison stars, we find 8 r-II stars and 35 r-I stars. The r-II stars, including the two previously known examples CS 22892-052 and CS 31082-001, are centred on a metallicity of Fe/H = -2.81, with a very small scatter, on the order of 0.16 dex. The r-I stars are found across practically the entire metallicity range of our sample. We also find three stars with strong enhancements of Eu which are s-process rich. A significant number of new very metal-poor stars are confirmed: 49 stars with Fe/H < -3 and 181 stars with -3 < Fe/H < -2. We find one star with Fe/H < -3.5. We find the scatter in the abundance ratios of Mg, Ca, Sc, Ti, Cr, Fe, Co, and Ni, with respect to Fe and Mg, to be similar to the estimated relative errors and thus the cosmic scatter to be small, perhaps even non-existent. The elements C, Sr, Y, Ba and Eu, and perhaps Zr, show scatter at Fe/H QQQ ? -2.5 significantly larger than can be explained from the errors in the analysis, implying scatter which is cosmic in origin. Significant scatter is observed in abundance ratios between light and heavy neutron-capture elements at low metallicity and low levels of r-process enrichment.
Background
Lymph node status in colon cancer is critical for prognosis estimation and treatment allocation. The purpose of this study was to compare the performance of one-step nucleic acid ...amplification (OSNA) through detection of cytokeratin 19 mRNA levels with routine pathological examination (RP) and multilevel fine pathological examination (FP) in sentinel lymph nodes (SLN), detected using the ex vivo SLN mapping (SLNM) procedure, in presurgically defined nonmetastatic colon cancer patients.
Methods
In this prospective study, 325 SLNs of 128 patients from the Jeroen Bosch Hospital in ‘s-Hertogenbosch and the Leiden University Medical Center were investigated by RP (H&E), FP (H&E and Keratin Pan immunohistochemical staining), and OSNA. The SLNs were harvested by the SLNM procedure, using Patent blue or Indocyanine green. SLNs were divided and separate parts were used for RP, FP, and the OSNA assay.
Results
The diagnostic value of OSNA was 82.1 and 100 % for both FP and combined method (OSNA and FP) compared with RP. An upstaging rate of 20.2 % was obtained with the use of OSNA only and 36.4 % with the use of FP only. An upstaging rate of 46.5 % was obtained by combining the two methods together.
Conclusions
OSNA and FP appeared to be promising tools for the detection of lymph node micro- and macrometastases in SLNs after SLNM. The performances of OSNA and FP in this study were superior to RP. Because OSNA allows analysis of the whole lymph node, sampling bias can be avoided. OSNA therefore may improve tumor staging.
We report the discovery and high-resolution, high-S/N spectroscopic analysis of the ultra-metal-poor red giant HE 0557-4840, which is the third most heavy-element-deficient star currently known. Its ...atmospheric parameters are unk = 4900 K, log g = 2.2, and Fe/H = -4.75. This brings the number of stars with Fe/H < -4.0 to three, and the discovery of HE 0557-4840 suggests that the metallicity distribution function of the Galactic halo does not have a "gap" between Fe/H = -4.0, where several stars are known, and the two most metal-poor stars, at Fe/H similar to -5.3. HE 0557-4840 is carbon rich (O/Fe = +1.6), a property shared by all three objects with Fe/H < -4.0, suggesting that the well-known increase of carbon relative to iron with decreasing Fe/H reaches its logical conclusion (ubiquitous carbon richness) at lowest abundance. We also present abundances (nine) and limits (nine) for a further 18 elements. For species having well-measured abundances or strong upper limits, HE 0557-4840 is "normal" in comparison with the bulk of the stellar population at Fe/H similar to -4.0, with the possible exception of Co. We discuss the implications of these results for chemical enrichment at the earliest times, in the context of single- ("mixing and fallback") and two-component enrichment models. While neither offers a clear solution, the latter appears closer to the mark. Further data are required to determine the oxygen abundance and improve that of Co, and hence more strongly constrain the origin of this object.
We present a sample of 1777 bright (9 < B < 14) metal-poor candidates selected from the Hamburg/ESO Survey (HES). Despite saturation effects present in the red portion of the HES objective-prism ...spectra, the data were recoverable and quantitative selection criteria could be applied to select the sample. Analyses of medium-resolution (62 AA) follow-up spectroscopy of the entire sample, obtained with several 2-4 m class telescopes, yielded 145 new metal-poor stars with metallicity Fe/H < -2.0, of which 79 have Fe/H < -2.5 and 17 have Fe/H < -3.0. We also obtained C/Fe estimates for all of these stars. From this, we find a frequency of C-enhanced (C/Fe > 1.0) metal-poor (Fe/H < -2.0) giants of 9% c 2%, which is lower than previously reported. However, the frequency rises to similar (>20%) and higher values with increasing distance from the Galactic plane. Although the numbers of stars at low metallicity are falling rapidly at the lowest metallicities, there is evidence that the fraction of carbon-enhanced metal-poor stars is increasing rapidly as a function of declining metallicity. For 660 objects, high-resolution data have already been obtained; one of these, HE 1327-2326, is the new record holder for the most iron-deficient star known.
Abstract Few randomized controlled trials (RCTs) and observational studies had shown acceptable short-term efficacy and safety of percutaneous coronary intervention (PCI) with drug eluting stents ...(DES) as compared to coronary artery bypass grafting (CABG) in selected patients with left main coronary artery disease (LMCAD). We aimed to evaluate long-term outcomes of PCI using DES compared with CABG in patients with LMCAD. On November 1st , 2016, we searched available databases for published RCTs directly comparing DES PCI with CABG in patients with LMCAD. Odds ratios (OR) were used as the metric of choice for treatment effects using a random-effects models. I-squared index was used to assess heterogeneity across trials. Pre-specified end-points were all-cause mortality, cardiovascular mortality, myocardial infarction (MI), stroke and repeat revascularization at maximal available follow-up. We identified 5 RCTs including a total of 4,595 patients, with a median follow-up of 60 months. The risk of all-cause mortality OR 1.01; 95% CI 0.76-1.34 and cardiovascular mortality OR 1.02; 95% CI 0.73-1.42 were comparable between PCI with DES and CABG. Similarly, there were no statistically significant differences between PCI with DES and CABG for MI OR 1.45; 95% CI 0.87-2.40 and stroke OR 0.87; 95% CI 0.38-1.98. Conversely, repeat revascularization was significantly higher with PCI as compared with CABG OR 1.82; 95% CI 1.51-2.21. In conclusion, in patients with LMCAD, PCI with DES appears to be a viable alternative to CABG at long-term follow-up, with similar risks of ischemic adverse events (mortality, MI and stroke) but a higher risk of repeat revascularization.
Colorectal cancer (CRC) is the most commonly diagnosed cancer in Europe. Because CRC is also a major cause of cancer-related deaths worldwide, a lot of research has been focused on the discovery and ...development of biomarkers to improve the diagnostic process and to predict treatment outcomes. Up till now only a few biomarkers are recommended by expert panels. Current TNM criteria, however, cause substantial under- and overtreatment of CRC patients. Consequently, there is a growing need for new and efficient biomarkers to ensure optimal treatment allocation. An ideal biomarker should be easily translated into clinical practice, to identify patients who can be spared from treatment or benefit from therapy, ultimately resulting in precision medicine in the future. In this review we aim to provide an overview of a number of frequently studied biomarkers in CRC and, at the same time, we will emphasize the challenges and controversies that withhold the clinical introduction of these biomarkers. We will discuss both prognostic and predictive markers of chemotherapy, aspirin therapy as well as overall therapy toxicity. Currently, only mutant KRAS, mutant BRAF, MSI and the Oncotype DX® Colon Cancer Assay are used in clinical practice. Other biomarker studies showed insufficient evidence to be introduced into clinical practice. Divergent patient selection criteria, absence of validation studies and a large number of single biomarker studies are possibly responsible. We therefore recommend that future studies focus on combining key markers, rather than analysing single markers, standardizing study protocols, and validate the results in independent study cohorts, followed by prospective clinical trials.
Pump–probe experiments at X‐ray free‐electron laser (XFEL) facilities are a powerful tool for studying dynamics at ultrafast and longer timescales. Observing the dynamics in diverse scientific cases ...requires optical laser systems with a wide range of wavelength, flexible pulse sequences and different pulse durations, especially in the pump source. Here, the pump–probe instrumentation available for measurements at the Single Particles, Clusters, and Biomolecules and Serial Femtosecond Crystallography (SPB/SFX) instrument of the European XFEL is reported. The temporal and spatial stability of this instrumentation is also presented.
The pump–probe capabilities at the SPB/SFX instrument of the European XFEL are discussed.
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