The variant rs4769613 T/C within the enhancer element near FLT1 , an acknowledged gene in preeclampsia, was previously identified as a risk factor for preeclampsia in the genome-wide association study (GWAS) targeting placental genotypes. We aimed to test the robustness of this association in 2 Estonian cohorts. Both placental sample sets HAPPY PREGNANCY (Development of novel non-invasive biomarkers for fertility and healthy pregnancy; preeclampsia, n=44 versus nonpreeclampsia, n=1724) and REPROMETA (REPROgrammed fetal and/or maternal METAbolism; 52/277) exhibited suggestive association between rs4769613[C] variant and preeclampsia (logistic regression adjusted for gestational age and fetal sex, nominal P <0.05). Meta-analysis across 2 samples (96/2001) replicated the genome-wide association study outcome (Bonferroni corrected P =4×10 -3 ; odds ratio, 1.75 [95% CI, 1.23–2.49]). No association was detected with gestational diabetes mellitus, preterm birth, and newborn parameters. Also, neither maternal nor paternal rs4769613 genotypes predisposed to preeclampsia. The exact role of placental rs4769613 genotype in the preeclampsia pathogenesis is to be clarified as no effect was detected on maternal baseline serum sFlt-1 (soluble fms-related receptor tyrosine kinase 1) levels. However, when placental FLT1 gene expression and maternal serum sFlt-1 measurements were stratified by placental rs4769613 genotypes, significantly higher transcript and biomarker levels were detected in preeclampsia versus nonpreeclampsia cases in the CC- and CT- (Student t test, P ≤0.02), but not in the TT-genotype subgroup. We suggest that rs4769613 represents a conditional expression Quantitative Trait Locus, whereby only the enhancer with the C-allele reacts to promote the FLT1 expression in unfavorable placental conditions. The study highlighted that the placental FLT1 rs4769613 C-allele is a preeclampsia-specific risk factor. It may contribute to early identification of high-risk women, for example, when genotyped in the cffDNA available in maternal blood plasma.
Background Preeclampsia (PE) affects 2%–8% of all pregnancies worldwide. The predictive value of the currently used maternal serum fms-like tyrosine kinase-1/ placental growth factor (sFlt-1/PlGF) test is < 40% for PE onset within 4 weeks. We aimed to develop an innovative multiplex assay to improve PE prediction. Methods The 6PLEX assay combining the measurements of ADAM12, sENG, leptin, PlGF, sFlt-1, and PTX3 was developed for the Luminex® xMAP platform. Assay performance was evaluated using 61 serum samples drawn from 53 pregnant women between 180 and 275 gestational days: diagnosed PE cases, n = 4; cases with PE onset within 4–62 days after sampling, n = 25; controls, n = 32. The B·R·A·H·M·S Kryptor sFlt-1/PlGF test (Thermo Fisher Scientific, Hennigsdorf, Germany) was applied as an external reference. Alternative PE prediction formulae combining 6PLEX measurements with clinical parameters were developed. Results There was a high correlation in sFlt-1/PlGF estimated for individual sera between the 6PLEX and B·R·A·H·M·S Kryptor immunoassays (Spearman’s r = 0.93, P < 0.0001). The predictive power of the 6PLEX combined with gestational age and maternal weight at sampling reached AUC 0.99 (95% CI 0.97–1.00) with sensitivity 100.0% and specificity 96.9%. In all models, sFlt-1/PlGF derived from the B·R·A·H·M·S immunoassays exhibited the lowest AUC value (<0.87) and sensitivity (<80%) with broad confidence intervals (13%–92%). The estimated prognostic yield of the 6PLEX compared to the B·R·A·H·M·S assay was significantly higher (96.5% vs 73.7%; P = 0.0005). Conclusions The developed single-tube multimarker assay for PE risk estimation in combination with clinical symptoms reached high prognostic yield (96.5%) and exhibited superior performance compared to the sFlt-1/PlGF test.
This study has evaluated the correlation between different carbapenemases detection methods on carbapenem non-susceptible Klebsiella pneumoniae strains from Northern and Eastern Europe; 31 institutions in 9 countries participated in the research project, namely Finland, Estonia, Latvia, Lithuania, Russia, St. Petersburg, Poland, Belarus, Ukraine, and Georgia. During the research program, a total of 5,001 clinical K. pneumoniae isolates were screened for any carbapenem non-susceptibility by the disk diffusion method, Vitek 2 or Phoenix system following the EUCAST guideline on detection of resistance mechanisms, version 1.0. Strains isolated from outpatients and hospitalized patients from April 2015 to June 2015 were included. All types of samples (blood, pus, urine, etc.) excluding fecal screening or fecal colonization samples have been represented. In total, 171 carbapenemase screening-positive K. pneumoniae isolates (3.42%) were found and characterized. Several methods were used for detection of carbapenemases production, including Luminex assay (PCR and hybridization), whole genome sequencing, MALDI-TOF based Imipenem degradation assay, and immunochromatography testing. Minimal inhibitory concentration determination for Meropenem by agar-based gradient method was also used. Finally, 83 K. pneumoniae strains were carbapenemase negative by all confirmation methods (49.4% of all screening-positive ones), 74 – positive by three methods (44.0%), 8 – positive by two methods (4.8%) and 3 – positive by only one method (1.8%). The sensitivity of the tests was 96.3% for Whole genome sequencing and MALDI-TOF assay (both three undetected cases), and 95.1% for Luminex-Carba (4 undetected cases). The most commonly detected carbapenemases were NDM ( n = 54) and OXA-48 ( n = 26), followed by KPC-2, VIM-5, and OXA-72 (one case of each). Our results showed that different types of carbapenemases can be detected in the countries involved in the project. The sensitivity of our methods for carbapenemase detection (including screening as a first step and further confirmation tests) was >95%, but we would recommend using different methods to increase the sensitivity of detection and make it more precise.
Due to their broad cell- and tissue-tropism, alphavirus-based replication-competent vectors are of particular interest for anti-cancer therapy. These properties may, however, be potentially hazardous unless the virus infection is controlled. While the RNA genome of alphaviruses precludes the standard control techniques, host miRNAs can be used to down-regulate viral replication. In this study, target sites from ubiquitous miRNAs and those of miRNAs under-represented in cervical cancer cells were inserted into replication-competent DNA/RNA layered vectors of Semliki Forest virus. It was found that in order to achieve the most efficient suppression of recombinant virus rescue, the introduced target sequences must be fully complementary to those of the corresponding miRNAs. Target sites of ubiquitous miRNAs, introduced into the 3′ untranslated region of the viral vector, profoundly reduced the rescue of recombinant viruses. Insertion of the same miRNA targets into coding region of the viral vector was approximately 300-fold less effective. Viruses carrying these miRNAs were genetically unstable and rapidly lost the target sequences. This process was delayed, but not completely prevented, by miRNA inhibitors. Target sites of miRNA under-represented in cervical cancer cells had much smaller but still significant effects on recombinant virus rescue in cervical cancer-derived HeLa cells. Over-expression of miR-214, one of these miRNAs, reduced replication of the targeted virus. Though the majority of rescued viruses maintained the introduced miRNA target sequences, genomes with deletions of these sequences were also detected. Thus, the low-level repression of rescue and replication of targeted virus in HeLa cells was still sufficient to cause genetic instability.
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