Recent whole-genome sequencing identified four molecular subtypes of gastric cancer (GC), of which the subgroup of Epstein–Barr virus-associated GC (EBVaGC) showed a significant enrichment of PIK3CA ...mutations. We here aimed to validate independently the enrichment of PIK3CA mutations in EBVaGC of a Central European GC cohort, to correlate EBV status with clinico-pathological patient characteristics and to test for a major issue of GC, intratumoral heterogeneity.
In a first step, 484 GCs were screened for EBV and PIK3CA hot spot mutations of exon 9/20 using EBER in situ hybridization and pyrosequencing, respectively. Secondly, an extended sequencing of PIK3CA also utilizing next generation sequencing was carried out in all EBVaGCs and 96 corresponding lymph node metastases.
Twenty-two GCs were EBER-positive, all being of latency type I. Intratumoral heterogeneity of EBER-positivity was found in 18% of EBVaGCs. Twenty-three GCs held PIK3CA mutations in hot spot regions of exon 9 or 20, being significantly more common in EBVaGCs (P<0.001). Subsequent extended sequencing of PIK3CA of EBVaGCs showed that 14% harvested three to five different PIK3CA genotypes (including wildtype) in the same primary tumor, albeit in histologically and spatially distinct tumor areas, and that intratumoral heterogeneity of PIK3CA was also present in the corresponding lymph node metastases.
Our findings unravel issues of tumor heterogeneity and illustrate that the assessment of the EBV status in tissue biopsies might carry the risk of sampling errors, which may significantly hamper adequate molecular tumor classification in a more clinical setting. Moreover, this is the first report of intratumoral heterogeneity of PIK3CA mutations in GC, and our findings lead to the conclusion that PIK3CA mutant and -wildtype tumor subclones are skilled to metastasize independently to different regional lymph nodes.
•Ginger and respective products are easily screened for bioactive compounds.•EDA is shown for radical scavengers, antimicrobials, estrogens, enzyme inhibitors.•HPTLC-HRMS allows streamlined bioactive ...compound verification.•Quantification of 6-gingerol and -shogaol is shown for different matrices.•LOD/LOQ of 6-gingerol and 6-shogaol are determined for UV/Vis/EDA.
Decision makers responsible for quality management along the food chain need to reflect on their analytical tools that should ensure quality of food and especially superfood. The “4ables” in target analysis (stable, extractable, separable, detectable) focusing on marker compounds do not cover all relevant information about the sample. On the example of ginger, a streamlined quantitative bioprofiling was developed for effect-directed analysis of 17 commercially available ginger and ginger-containing products via high-performance thin-layer chromatography (HPTLC-UV/Vis/FLD-bioassay). The samples were investigated concerning their active profile as radical scavengers, antimicrobials, estrogen-like activators and acetylcholinesterase/tyrosinase inhibitors. The 6-gingerol and 6-shogaol content of the different products ranged 0.2–7.4mg/g and 0.2–3.0mg/g, respectively. Further, multipotent compounds were discovered, characterized, and for example, assigned as 8- and 10-gingerol via HPTLC-ESI-HRMS. The developed bioprofiling is a step forward to new analytical methods needed to inform on the true product quality influenced by cultivation, processing, and storage.
Postoperative delirium in elderly patients is a frequent complication and associated with poor outcome. The aim of this parallel group study was to determine whether monitoring depth of anaesthesia ...influences the incidence of postoperative delirium.
Patients who were planned for surgery in general anaesthesia expected to last at least 60 min and who were older than 60 yr were included between March 2009 and May 2010. A total of 1277 patients of a consecutive sample were randomized (n=638 open, n=639 blinded) and the data of 1155 patients were analysed (n=575 open, n=580 blinded). In one group, the anaesthesiologists were allowed to use the bispectral index (BIS) data to guide anaesthesia, while in the other group, BIS monitoring was blinded. Cognitive function was evaluated at baseline, 1 week, and 3 months after operation.
Delirium incidence was lower in patients guided with BIS. Postoperative delirium was detected in 95 patients (16.7%) in the intervention group compared with 124 patients (21.4%) in the control group (P=0.036). In a multivariate analysis, the percentage of episodes of deep anaesthesia (BIS values <20) were independently predictive for postoperative delirium (P=0.006; odds ratio 1.027). BIS monitoring did not alter the incidence of postoperative cognitive dysfunction (7th day P=0.062; 90th day P=0.372).
Intraoperative neuromonitoring is associated with a lower incidence of delirium, possibly by reducing extreme low BIS values. Therefore, in high-risk surgical patients, this may give the anaesthesiologist a possibility to influence one precipitating factor in the complex genesis of delirium.
ISRCTN Register: 36437985. http://www.controlled-trials.com/ISRCTN36437985/.
We analyzed whether co-occurring mutations influence the outcome of systemic therapy in ALK-rearranged non-small-cell lung cancer (NSCLC).
ALK-rearranged stage IIIB/IV NSCLC patients were analyzed ...with next-generation sequencing and fluorescence in situ hybridization analyses on a centralized diagnostic platform. Median progression-free survival (PFS) and overall survival (OS) were determined in the total cohort and in treatment-related sub-cohorts. Cox regression analyses were carried out to exclude confounders.
Among 216 patients with ALK-rearranged NSCLC, the frequency of pathogenic TP53 mutations was 23.8%, while other co-occurring mutations were rare events. In ALK/TP53 co-mutated patients, median PFS and OS were significantly lower compared with TP53 wildtype patients PFS 3.9months (95% CI: 2.4–5.6) versus 10.3months (95% CI: 8.6–12.0), P<0.001; OS 15.0months (95% CI: 5.0–24.9) versus 50.0months (95% CI: 22.9–77.1), P=0.002. This difference was confirmed in all treatment-related subgroups including chemotherapy only PFS first-line chemotherapy 2.6months (95% CI: 1.3–4.1) versus 6.2months (95% CI: 1.8–10.5), P=0.021; OS 2.0months (95% CI: 0.0–4.6) versus 9.0months (95% CI: 6.1–11.9), P=0.035, crizotinib plus chemotherapy PFS crizotinib 5.0months (95% CI: 2.9–7.2) versus 14.0months (95% CI: 8.0–20.1), P<0.001; OS 17.0months (95% CI: 6.7–27.3) versus not reached, P=0.049 and crizotinib followed by next-generation ALK-inhibitor PFS next-generation inhibitor 5.4months (95% CI: 0.1–10.7) versus 9.9months (95% CI: 6.4–13.5), P=0.039; OS 7.0months versus 50.0months (95% CI: not reached), P=0.001).
In ALK-rearranged NSCLC co-occurring TP53 mutations predict an unfavorable outcome of systemic therapy. Our observations encourage future research to understand the underlying molecular mechanisms and to improve treatment outcome of the ALK/TP53 co-mutated subgroup.
Solution to element crossword challenge Krüger, S.; Hattendorf, B.
Analytical and bioanalytical chemistry,
10/2020, Letnik:
412, Številka:
25
Journal Article
Intermediate depth seismicity in subduction zones often occurs in the form of two slab‐parallel bands. We estimated the seismic P to S wave velocity ratio within the shallowest part of the lower ...seismicity zone (LSZ) in the mantle of the subducting slab of the Central Andean subduction system at 50‐km depth, 30 km below the Moho, using local earthquake data. We find an exceptionally high VP/VS value larger than ∼2.0 that cannot be explained by a realistic solid lithology but requires the presence of fluid‐filled porosity. This implies that the incoming Nazca plate must be partially hydrated to this depth below the seafloor. We introduce a state‐of‐the‐art petrophysical model that takes into account the thermodynamic and poroelastic effects of dynamic metamorphic mineral dehydration at 1.8 GPa and consider anisotropic effects. The model shows that a high VP/VS value generally indicates that the medium is near the percolation threshold, that is, that porosity must be interconnected. This result is consistent with observations from outcrops of paleosubduction zones, laboratory experiments, and numerical simulations. It follows that the shallowest part of the LSZ of the Central Andes must reside at a temperature at which mineral dehydration reactions take place, here between 430 and 500 ° C. For the first time, we can confirm that the observations of transient dehydrating fluid‐filled vein structures with a pore volume in the order of only 10−3 are reasonable for the LSZ and enough to allow for effective drainage.
Plain Language Summary
Beneath the Central Andes, small earthquakes occur along a band 30 km within the subducting Nazca tectonic plate that slowly sinks below the South American plate. Such earthquake bands occur worldwide, and it has been proposed that they happen, because there is water bound in the solid rocks there, which would be released when the subducting plate heats up while it sinks into the Earth. We test this hypothesis by determining a rock property that can indicate whether liquid water is present from the arrival times of earthquake waves. We then theoretically calculate how this property would be for different kinds of rock that can be present at this specific location within the Earth. It results that the rock property that we derived in the earthquake band can best be explained by the presence of liquid water that is stored in thin interconnected veins there. Other researchers saw in laboratory experiments, in computer simulations, and in the field that rocks that release water look exactly like this, so that their and our pieces of the puzzle fit together well. With this knowledge, we can understand better how water sinks into the Earth and how it finds its way back to the surface.
Key Points
A high seismic VP/VS ratio is observed in a lower band of seismicity in a subducting slab
Active metamorphic mineral dehydration is required to explain this value
Poroelastic modeling indicates the presence of a percolating vein network
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